Morpholin-acetamide derivatives for the treatment of inflammatory diseases

ABSTRACT

There are provided according to the invention, novel compounds of formula (I)  
                 
 
wherein R 1 , R 2 , R 3 , R 4 , R 5 , X, a, b and Z are as defined in the specification, processes for preparing them, formulations containing them and their use in therapy for the treatment of inflammatory diseases.

This invention relates to novel chemical compounds, processes for theirpreparation, pharmaceutical formulations containing them and their usein therapy.

Inflammation is a primary response to tissue injury or microbialinvasion and is characterised by leukocyte adhesion to the endothelium,diapedesis and activation within the tissue. Leukocyte activation canresult in the generation of toxic oxygen species (such as superoxideanion), and the release of granule products (such as peroxidases andproteases). Circulating leukocytes include neutrophils, eosinophils,basophils, monocytes and lymphocytes. Different forms of inflammationinvolve different types of infiltrating leukocytes, the particularprofile being regulated by the profile of adhesion molecule, cytokineand chemotactic factor expression within the tissue.

The primary function of leukocytes is to defend the host from invadingorganisms, such as bacteria and parasites. Once a tissue is injured orinfected, a series of events occurs which causes the local recruitmentof leukocytes from the circulation into the affected tissue. Leukocyterecruitment is controlled to allow for the orderly destruction andphagocytosis of foreign or dead cells, followed by tissue repair andresolution of the inflammatory infiltrate. However in chronicinflammatory states, recruitment is often inappropriate, resolution isnot adequately controlled and the inflammatory reaction causes tissuedestruction. There is increasing evidence that the bronchialinflammation which is characteristic of asthma represents a specialisedform of cell-mediated immunity, in which cytokine products, such as IL-4and IL-5 released by Th2 T lymphocytes, orchestrate the accumulation andactivation of granulocytes, in particular eosinophils and to a lesserextent basophils. Through the release of cytotoxic basic proteins,pro-inflammatory mediators and oxygen radicals, eosinophils generatemucosal damage and initiate mechanisms that underlie bronchialhyperreactivity. Therefore, blocking the recruitment and activation ofTh2 cells and eosinophils is likely to have anti-inflammatory propertiesin asthma. In addition, eosinophils have been implicated in otherdisease types such as rhinitis, eczema, irritable bowel syndrome andparasitic infections.

Chemokines are a large family of small proteins which are involved intrafficking and recruitment of leukocytes (for review see Luster, NewEng. J. Med., 338, 436-445 (1998)). They are released by a wide varietyof cells and act to attract and activate various cell types, includingeosinophils, basophils, neutrophils, macrophages, T and B lymphocytes.There are two major families of chemokines, CXC-(α) and CC-(β)chemokines, classified according to the spacing of two conservedcysteine residues near to the amino terminus of the chemokine proteins.Chemokines bind to specific cell surface receptors belonging to thefamily of G-protein-coupled seven transmembrane-domain proteins (forreview see Luster, 1998). Activation of chemokine receptors results in,amongst other responses, an increase in intracellular calcium, changesin cell shape, increased expression of cellular adhesion molecules,degranulation and promotion of cell migration (chemotaxis).

To date, 9 members of CC chemokine receptors have been identified (CCR-1to 9). Of particular importance to the current invention is theCC-chemokine receptor-3 (CCR-3), which is predominantly expressed oneosinophils, and also on basophils, mast cells and Th2 cells (Luster,1998). Chemokines that act at CCR-3, such as RANTES, MCP-3 and MCP-4,are known to recruit and activate eosinophils. Of particular interestare eotaxin and eotaxin-2, which specifically bind to CCR-3. Thelocalization and function of CCR-3 chemokines indicate that they play acentral role in the development of allergic diseases such as asthma.Thus, CCR-3 is specifically expressed on all the major cell typesinvolved in inflammatory allergic responses. Chemokines that act atCCR-3 are generated in response to inflammatory stimuli and act torecruit these cell types to sites of inflammation, where they causetheir activation (e.g. Griffiths et al., J. Exp. Med., 179, 881-887(1994), Lloyd et al., J. Exp. Med., 191, 265-273 (2000)). In addition,anti-CCR-3 monoclonal antibodies completely inhibit eotaxin interactionwith eosinophils (Heath, H. et al., (1997) J. Clin. Invest. 99 (2),178-184), while an antibody for the CCR-3 specific chemokine, eotaxin,reduced both bronchial hyperreactivity and lung eosinophilia in ananimal model of asthma (Gonzalo et al., J. Exp. Med., 188, 157-167(1998). Thus, many lines of evidence indicate that antagonists at theCCR-3 receptor are very likely to be of therapeutic use for thetreatment of a range of inflammatory conditions.

A number of patent applications relating to CCR-3 antagonists havepublished before the filing date of this application. For example, EP 0903 349, FR 2785902, WO 00129377, WO 00/31032 and WO 00/31033 (all inthe name of F. Hoffmann-La-Roche AG) disclose pyrrolidine, piperidineand piperazine based compounds which are all distinct from the compoundsof the present invention.

-   WO 99/55324, WO 00/04003, WO 00/27800, WO 00/27835, WO 00/27843, WO    00/41685 and WO 00/53172 (all in the name of SmithKline Beecham    Corporation) describe a variety of compounds as CCR-3 antagonists    which are unrelated to the compounds of the present invention.-   WO 00/34278 (Toray Industries Inc.) describe fused triazolo derived    compounds as chemokine inhibitors.-   WO 00/35449, WO 00/35451, WO 00/35452, WO 00/35453, WO 00/35454, WO    00/35876 and WO 00/35877 (Du Pont Pharmaceuticals Company) describe    N-ureidoalkyl and heterocyclic piperidine compounds as CCR-3    antagonists.-   WO 00151607 and WO 00/51608 (Merck & Co. Inc.) describe a series of    pyrrolidine modulators of chemokine receptor activity.-   WO 00/53600 (Banyu Pharmaceutical Co. Ltd.) describes piperidine    derivatives as inhibitors at the CCR-3 receptor.-   WO 01/14333 (AstraZeneca UK Ltd.) describe substituted piperidine    compounds as modulators of chemokine receptor activity.-   EP 0 760 362 (Nisshin Flour Milling Co. Ltd.) describes    morpholinoalkylurea derivatives which are disclosed as being useful    in the treatment of digestive tract diseases.-   JP 04208267A (Mitsui Seiyaku Kogyo KK) also describes    morpholinoalkylurea derivatives which are disclosed as being useful    as antiemetics, for activating peristalsis and ameliorating    gastrointestinal function.-   EP 243959A (Dainippon Pharm KK) describes O-substituted    N-morpholinyl-alkyl-benzamide derivatives useful as gastrointestinal    motility enhancing agents.-   J0 1117-882-A (Dainippon Pharm KK) describes heterocyclic    morpholinyl alkylenyl carboxamide derivatives useful as    anti-emetics.-   WO 00/71518 (Sepracor Inc) describes morpholinoalkylamide    derivatives useful in the treatment of pain, drug addiction and    tinnitus.-   WO 97/48695 and WO 97/48397 (Klinge Pharma Gmbh) describe pyridyl    alkane, alkene and/or alkyne acid amide compounds useful as    cytostatic, immunomodulatory or immuno-suppressive agents.-   Kato et al., (1992) Chem. Pharm. Bull. 40(3), 652-660, Kato et    al., (1991) J. Med. Chem. 34(2), 616-624 and Kato et al., (1990) J.    Med. Chem.33(5), 1406-1413 describe a series of morpholine    benzamides which are disclosed as being selective and potent    gastrokinetic agents.

We have now found a novel group of CCR-3 antagonist compounds whichblock migration/chemotaxis of eosinophils, consequently effectinganti-inflammatory properties. These compounds are therefore of potentialtherapeutic benefit, especially in providing protection from eosinophil,basophil and Th2-cell-induced tissue damage in diseases where such celltypes are implicated, particularly allergic diseases, including but notlimited to bronchial asthma, allergic rhinitis and atopic dermatitis.

In addition to a key role in inflammatory disorders, chemokines andtheir receptors also play a role in infectious disease. Mammaliancytomegaloviruses, herpes viruses and pox viruses express chemokinereceptor homologues, which can be activated by human CC chemokines suchas RANTES and MCP-3 (for review see Wells and Schwartz, Curr. Opin.Biotech., 8, 741-748, 1997). In addition, human chemokine receptors,such as CXCR4, CCR-5 and CCR-3, can act as co-receptors for theinfection of mammalian cells by microbes such as human immunodeficiencyviruses (HIV). CCR-3 serves as a co-receptor for certain clinicalstrains of HIV-1 and facilitates viral entry (e.g Choe, H. et al, Cell,1996, 85, 1135-1148). A key ligand for CCR-3, eotaxin, blocked theprocess of HIV entry. Thus, chemokine receptor antagonists, includingCCR-3 antagonists, may be useful in blocking infection of CCR-3expressing cells by HIV or in preventing the manipulation of immunecellular responses by viruses such as cytomegaloviruses.

Thus, according to one aspect of the invention, we provide compounds offormula (I):

wherein:

R¹ represents C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₂₋₆ alkynyl-Y¹—,aryl-Y¹—, heteroaryl-Y¹—, aryl-(O)_(t)-aryl-Y¹—,aryl-(O)_(t)-heteroaryl-Y¹—, heteroaryl-(O)_(t)-aryl-Y¹—,heteroaryl-(O)_(t)-heteroaryl-Y¹—, C₂₋₆ alkenyl-Y¹—, aryl-O—Y¹—,heteroaryl-O—Y¹—, C₁₋₆ alkyl-SO₂—Y¹—, M-Y¹—, J²-Y¹—, —CN or C₃₋₈cycloalkyl-Y¹— or C₃₋₈ cycloalkenyl-Y¹—, which cycloalkyl orcycloalkenyl may be optionally substituted by one or more hydroxyl orC₁₋₆ alkyl groups;

R² represents hydrogen or C₁₋₆ alkyl;

X represents ethylene or a group of formula CR^(e)R^(f) wherein R^(e)and R^(f) independently represent hydrogen or C₁₋₄ alkyl or R^(e) andR^(f) may together with the carbon atom to which they are attached forma C₃₋₈ cycloalkyl group;

R³ and R⁴ independently represent hydrogen or C₁₋₄ alkyl;

Z represents a bond, CO, SO₂, CR⁹R⁶(CH₂)_(n), (CH₂)_(n)CR⁹R⁶,CHR⁶(CH₂)_(n)O, CHR⁶(CH₂)_(n)S, CHR⁶(CH₂)_(n)OCO, CHR⁶(CH₂)_(n)CO,COCHR⁶(CH₂)_(n) or SO₂CHR⁶(CH)_(n);

R⁵ represents C₁₋₄ alkyl, C₂₋₆ alkenyl, aryl, heteroaryl, aryl-C₂₋₆alkenyl- or a group of formula —Y²-J¹;

R⁶ represents hydrogen, C₁₋₄ alkyl, CONR⁷R⁸ or COOC₁₋₆ alkyl;

a and b represent 1 or 2, such that a+b represents 2 or 3;

n represents an integer from 0 to 4;

J¹ and J² independently represent a moiety of formula (K):

wherein X¹ represents oxygen, NR¹³ or sulphur, X² represents CH₂,oxygen, NR¹⁰ or sulphur, m¹ represents an integer from 1 to 3 and m²represents an integer from 1 to 3, provided that m¹+m² is in the rangefrom 3 to 5, also provided that when both X¹ and X² represent oxygen,NR¹³, NR¹⁰ or sulphur, m¹ and m² must both not equal less than 2,wherein K is optionally substituted by one or more (eg. 1 or 2)—Y³-aryl, —Y³-heteroaryl, —Y³—CO-aryl, —COC₃₋₈cycloalkyl,—Y³—CO-heteroaryl, —C₁₋₆ alkyl, —Y³—COOC₁₋₆ alkyl, —Y³—COC₁₋₆ alkyl,—Y³—W, —Y³—CO—W, —Y³—NR¹¹R¹², —Y³—CONR¹¹R¹², hydroxy, oxo,—Y³—SO₂NR¹¹R¹², —Y³—SO₂C₁₋₆ alkyl, —Y³—SO₂aryl, —Y³—SO₂heteroaryl,—Y³—NR¹⁴C₁₋₆ alkyl, —Y³—NR¹⁴SO₂C₁₋₆ alkyl, —Y³—NR¹⁴CONR¹¹R¹²,—Y³—NR¹⁴COOR¹⁵ or —Y³—OCONR¹¹R¹² groups, and is optionally fused to amonocyclic aryl or heteroaryl ring;

R⁷, R⁸, R⁹, R¹⁰, R¹³, R¹⁴ and R¹⁵ independently represent hydrogen orC₁₋₆ alkyl;

R¹¹ and R¹² independently represent hydrogen or C₁₋₆ alkyl or R¹¹ andR¹² together with the nitrogen atom to which they are attached may forma morpholine, piperidine or pyrrolidine ring;

M represents a C₃₋₈ cycloalkyl or a C₃₋₈ cycloalkenyl group fused to amonocyclic aryl or monocyclic heteroaryl group;

W represents a saturated or unsaturated, non-aromatic 5-7 membered ringcontaining between 1 and 3 heteroatoms selected from nitrogen, oxygen orsulphur, optionally substituted with one or more C₁₋₆ alkyl, halogen orhydroxy groups;

t represents 0 or 1.

Y¹, Y² and Y³ independently represent a bond or a group of formula—(CH₂)_(p)CR^(c)R_(d)(CH₂)_(q)— wherein R^(c) and R^(d) independentlyrepresent hydrogen or C₁₋₄ alkyl or R^(c) and R_(d) may together withthe carbon atom to which they are attached form a C₃₋₈ cycloalkyl group,and p and q independently represent an integer from 0 to 5 wherein p+qis an integer from 0 to 5;

and salts and solvates thereof.

Specific groups of compounds of formula (I) which may be mentioned arethose as defined above with the proviso that the compound of formula (I)is not a compound of formula (I)^(a):

wherein R^(ai) represents hydrogen, halogen, nitro, SO₂NH₂, or mono- ordi-(C₁₋₄ alkylsulphamoyl; R^(bi) represents hydrogen, halogen, amino,nitro, —N(CH₃)₂ or C₂₋₅ alkanoylamino (provided that at least one ofR^(ai) and R^(bi) is not hydrogen); R^(ci) represents halogen, hydroxy,C₁₋₆ alkoxy, cyano, C₃₋₆ cycloalkyl, —SCH₃, amino or C₂₋₅alkoxycarbonyl; X^(i) represents methylene or ethylene; b^(i) represents1 or 2; R^(3i) and R^(4i) represent hydrogen or C₁₋₄ alkyl; and whereinthe moiety -Z^(i)-R^(5i) represents heteroarylC₁₋₃ alkyl (whereinheteroaryl represents furyl, thienyl, pyridyl or 1,2-benzisoxazolyl),phenyl-C₃₋₅ alkenyl, naphthyl, —C₁₋₅ alkylenenaphthyl, —C₁₋₅alkyleneonaphthyl, —C₁₋₅ alkyleneCOnaphthyl, phenyl, —C₁₋₅alkylenephenyl, —C₁₋₅ alkyleneophenyl or —C₁₋₅ alkyleneCOphenyl (whereinphenyl is substituted by one to five members each independently selectedfrom the group consisting of a halogen, C₁₋₄ alkyl, trifluoromethyl,C₁₋₄ alkoxy, nitro, cyano or amino) (compounds of formula (I)^(a) aredescribed in EP0243959A1); and/or

the proviso that the compound of formula (I) is not a compound offormula (I)^(b):

wherein Het represents a heteroaryl moiety; R^(aii), R^(bii) and R^(cii)represent hydrogen, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, amino or NMe₂;X^(ii) represents methylene or ethylene; R^(3ii) represents hydrogen orC₁₋₄ alkyl; b^(ii) represents 1 or 2; and wherein the moiety-Z^(ii)-R^(ii) represents optionally substituted aryl-C₁₋₅ alkyl-(compounds of formula (I)^(b) are described in J01117-882A); and/or

the proviso that the compound of formula (I) is not a compound offormula (I)^(c):

wherein R^(1ii) represents C₁₋₆ alkyl, C₃₋₈ cycloalkyl, heteroaryl oraryl; R^(2iii) represents C₁₋₄ alkyl; X^(iii) represents ethylene or agroup of formula CR^(eiii)R^(fiii) wherein R^(eiii) and R^(fiii)independently represent hydrogen or C₁₋₄ alkyl; R^(3iii) representshydrogen or C₁₋₄ alkyl; b^(iii) represents 1 or 2; Z^(iii) representsCR^(9iii) R^(6iii)(CH₂)_(niii) (wherein R^(6iii) represents hydrogen orC₁₋₄ alkyl and R^(9iii) represents hydrogen or C₁₋₆ alkyl and niiirepresents 0 to 3); and R^(5iii) represents C₁₋₆ alkyl, aryl, heteroarylor C₂₋₆ alkenyl (compounds of formula (I)^(c) are described inWO00/71518A2); and/or

the proviso that the compound of formula (I) is not a compound offormula (I)^(d):

wherein R^(aiv) represents hydrogen, halogen, —CN, —CF₃, —OH, —CONH₂,—COOH, C₁₋₄ alkyl, —C₂₋₆ alkenyl, —C₁₋₆ alkoxy, —SCH₃, C₃₋₈ cycloalkyl,—COOC₁₋₄ alkyl, —NHCOC₁₋₆ alkyl, —CON(C₁₋₆ alkyl)₂, —N(CH₃)₂; R^(biv)represents hydrogen, halogen, —CN, OH, —CF₃, C₁₋₆ alkyl or C₁₋₆ alkoxy;R^(civ) represents hydrogen, halogen, C₁₋₆ alkyl, —CF₃; Y^(1iv)represents C₁₋₆ alkylene; R^(2iv) represents hydrogen or C₁₋₆ alkyl;X^(iv) represents methylene or ethylene; R^(3iv) represents hydrogen orC₁₋₄ alkyl; R^(4iv) represents hydrogen or C₁₋₄ alkyl; b^(iv) represents2; Z^(iv) represents CR^(9iv)NR^(6iv)(CH₂)_(niv), CHR^(6iv)(CH₂)_(niv)CO(wherein R^(6iv) represents hydrogen or C₁₋₄ alkyl and R^(9iv)represents hydrogen or methyl and niv represents 0 to 3) orSO₂CHR^(6iv)(CH₂)_(niv) (wherein R^(6iv) represents hydrogen and nivrepresents 0); and R^(5iv) represents C₁₋₄ alkyl, C₃₋₆ alkenyl, phenyl,J¹ or heteroaryl (wherein said phenyl or heteroaryl may be optionallysubstituted by 1-3 halogen, CN, C₁₋₆ alkyl, —CF₃, C₃₋₈ cycloalkyl,hydroxy, C₁₋₆ alkoxy, —SCH₃, COOH, COOC¹⁻⁶ alkyl, nitro, amino or—N(CH₃)₂) (compounds of formula (I)^(d) are described in WO97/48695A1and WO97/48397A1); and/or

the proviso that the compound of formula (I) is not a compound offormula (I)^(e):

wherein R^(av) represents chlorine; R^(bv) represents amino; R^(cv)represents methoxy or ethoxy; and the moiety -Z^(v)R^(5v) representsphenyl or C₁₋₆ alkyl (such compounds of formula (I)^(e) are described inKato et al., (1992) Chem. Pharm. Bull. 40(3), 652-660);

-   also wherein R^(av) represents chlorine; R^(bv) represents amino;    R^(cv) represents methoxy or ethoxy; and the moiety -Z^(v)-R^(5v)    represents —CH₂-phenyl wherein phenyl is substituted by 2-, 3- or    4-chlorine, 2-, 3- or 4-fluorine, 3- or 4-CF₃, 3- or 4-methoxy,    4-methyl, 4-nitro, 4-amino, 4carboxymethyl, 3- or 4-cyano,    3,4-dichloro, 2,4-difluoro, 3,4-difluoro, 3,5-difluoro,    2,4,6-trimethyl (such compounds of formula (I)^(e) are described in    Kato et al., (1991) J. Med. Chem. 34(2), 616-624);-   also wherein R^(av) represents hydrogen, bromine, chlorine, nitro or    SO₂NH₂; R^(bv) represents amino, —NMe₂, —NEt₂ or —NHCOCH₃; R^(cv)    represents methoxy, ethoxy, hydroxy or chlorine; and the moiety    -Z^(v)-R^(5v) represents  CH₂-phenyl (such compounds of formula    (I)^(e) are described in Kato et al., (1990) J. Med. Chem. 33(5),    1406-1413).

A preferred set of compounds of formula (I) include compounds wherein R¹represents C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₂₋₆ alkynyl-Y¹—,aryl-Y¹—, heteroaryl-Y¹—, aryl-(O)_(t)-aryl-Y¹—,aryl-(O)_(t)-heteroaryl-Y¹—, heteroaryl-(O)_(t)-aryl-Y¹—,heteroaryl-(O)₁-heteroaryl-Y¹—, C₂₋₆ alkenyl-Y¹—, aryl-O—Y¹—,heteroaryl-O—Y¹—, C₁₋₆ alkyl-SO₂—Y¹—, M-Y¹— or C₃₋₈ cycloalkyl-Y¹— orC3-8 cycloalkenyl-Y¹—, which cycloalkyl or cycloalkenyl may beoptionally substituted by one or more hydroxyl or C₁₋₆ alkyl groups; and

J¹ represents a moiety of formula (K):

wherein X¹ represents oxygen, NR¹³ or sulphur, X² represents CH₂,oxygen, NR¹⁰ or sulphur, m¹ represents an integer from 1 to 3 and m²represents an integer from 1 to 3, provided that m¹+m² is in the rangefrom 3 to 5, also provided that when both X¹ and X² represent oxygen,NR¹³, NR¹⁰or sulphur, m¹ and m² must both not equal less than 2, whereinK is optionally substituted by one or more (eg. 1 or 2) —Y³-aryl,—Y³-heteroaryl, —Y³—CO-aryl, —Y³—CO-heteroaryl, —C₁₋₈ alkyl, —Y³—COOC₁₋₆alkyl, —Y³—COC₁₋₆ alkyl, —Y³—W, —Y³—CO—W, —Y³—NR¹¹R¹² ₁, —Y³—CONR¹¹R¹²,hydroxy, oxo, —Y³—SO₂NR¹¹R¹², —Y³—SO₂C₁₋₆ alkyl, —Y³—O₂aryl,—Y³—SO₂heteroaryl, —Y³—NR¹⁴C₁₋₆ alkyl, —Y³—NR¹⁴SO₂C₁₋₆ alkyl,—Y³—NR¹⁴CONR¹¹R¹², —Y³—NR¹⁴COOR¹⁵ or —Y³—OCONR¹¹R¹² groups, and isoptionally fused to a monocyclic aryl or heteroaryl ring.

A preferred subset of compounds of formula (I) include compounds whereinR¹ represents C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl-Y¹—,heteroaryl-Y¹—, aryl-(O)_(t)aryl-Y¹—, aryl-(O)_(t)-heteroaryl-Y¹—,heteroaryl-(O)^(t)-aryl-Y¹—, heteroaryl-(O)_(t)-heteroaryl-Y¹—, C₂₋₆alkenyl-Y¹—, aryl-O—Y¹, heteroaryl-O—Y¹—, C₁₋₆ alkyl-SO₂—Y¹—, M-Y¹— orC₃₋₈ cycloalkyl-Y¹— or C₃₋₈ cycloalkenyl-Y¹—, which cycloalkyl orcycloalkenyl may be optionally substituted by one or more hydroxyl orC₁₋₆ alkyl groups;

Z represents a bond, CO, CR⁹R⁶(CH₂)_(n), CHR⁶(CH₂)_(n)O, CHR⁶(CH₂)_(n)S,CHR⁶(CH₂)_(n)OCO, CHR⁸(CH₂)_(n)CO; and

J¹ represents a moiety of formula (K):

wherein X¹ represents oxygen, nitrogen, NR¹³ or sulphur, X² representsCH₂, oxygen, nitrogen, NR¹⁰ or sulphur, m¹ represents an integer from 1to 3, m² represents an integer from 1 to 3, provided that m¹+m² is inthe range from 3 to 5, also provided that when X² represents oxygen,nitrogen, NR¹⁰ or sulphur, m¹ and m² must both not equal less than 2,wherein K is optionally substituted by one or more (eg. 1 or 2)—Y³-aryl, —Y³-heteroaryl, —Y³—CO-aryl, —Y³—CO-heteroaryl, —C₁₋₆ alkyl,—Y³—COOC₁₋₆ alkyl, —Y³—COC₁₋₆ alkyl, —Y³—W, —Y³—CO—W, —Y³—NR¹¹R¹²,—Y³—CONR¹¹R¹², hydroxy, oxo, —Y³—SO₂NR¹¹R¹², —Y³—SO₂C₁₋₆ alkyl,—Y³—SO₂aryl, —Y³—SO₂heteroaryl, —Y³—NR¹⁴C₁₋₆ alkyl, —Y³—NR¹⁴SO₂C₁₋₆alkyl, —Y³—NR¹⁴CONR¹¹R¹², —Y³—NR¹⁴COOR¹⁵ or —Y³—OCONR¹¹R¹² groups, andis optionally fused to a monocyclic aryl or heteroaryl ring.

References to ‘aryl’ include references to monocyclic carbocyclicaromatic rings (eg. phenyl) and bicyclic carbocyclic aromatic rings(e.g. naphthyl) and references to ‘heteroaryl’ include references tomono- and bicyclic heterocyclic aromatic rings containing 1-3 heteroatoms selected from nitrogen, oxygen and sulphur. References to‘heteroaryl’ may also be extended to include references to mono- andbicyclic heterocyclic aromatic rings containing 4 hetero atoms selectedfrom nitrogen, oxygen and sulphur. Examples of monocyclic heterocyclicaromatic rings include e.g. pyridinyl, pyrimidinyl, thiophenyl, furanyl,pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl,imidazolyl. Further examples of monocyclic heterocyclic aromatic ringsinclude pyrazinyl or tetrazolyl. Examples of bicyclic heterocyclicaromatic rings include eg. benzimidazolyl, quinolinyl or indolyl.Further examples of bicyclic heterocyclic aromatic rings include eg.benzotriazolyl, pyrrolopyridine, benzothiazolyl and quinoxalinyl.Carbocyclic and heterocyclic aromatic rings may be optionallysubstituted, e.g. by one or more C₁₋₆ alkyl, C₂₋₆ alkenyl, halogen, C₁₋₆alkoxy, cyano, hydroxy, nitro, amino, W, —N(CH₃)₂, —NHCOC₁₋₆ alkyl,—OCF₃, —CF₃, —COOC₁₋₆ alkyl, —OCHF₂, —SCF₃, —SO₂N(CH₃)₂, —SO₂CH₃, —SCH₃,—CONR¹⁶R¹⁷ or —SO₂NR¹⁶R¹⁷ groups (wherein R¹⁶ and R¹⁷ independentlyrepresent hydrogen or C₁₋₆ alkyl; R¹⁶ and R¹⁷ may also independentlyrepresent C₃₋₈ cycloalkyl). Further substituents of carbocyclic andheterocyclic aromatic rings include —COOH and —NHSO₂CH₃. Yet furthersubstituents include —N(C₁₋₆alkyl)SO₂C₁₋₆alkyl, —N(SO₂C₁₋₆alkyl)₂,—NHCOCH₂N(C₁₋₄alkyl)₂, —NHCONHC₄alkyl, —CONH(CH₂)₂OC₁₋₆alkyl,—CONH(CH₂)₂N(C₁₋₆alkyl)₂, CON(C₁₋₆alkyl)₂, C₃₋₈cycloalkyl, morpholinyl,—COmethylpiperazinyl and COmorpholinyl.

Examples of group J¹ include indolinyl, which may be optionallysubstituted.

Examples of group J² include thiomorpholinyl and piperidinyl, which maybe optionally substituted, for example by t-butoxycarbonyl.

Examples of group M include tetrahydronaphthalenyl.

Examples of group W include piperidinyl, pyrrolidinyl, morpholinyl andpiperazinyl which may be optionally substituted.

References to alkyl include references to both straight chain andbranched chain aliphatic isomers of the corresponding alkyl. It will beappreciated that references to alkylene and alkoxy shall be interpretedsimilarly.

References to C₃₋₈ cycloalkyl include references to all alicyclic(including branched) isomers of the corresponding alkyl.

Preferably, R¹ represents C₁₋₆ alkyl (particularly butyl and—(CH₂)₂CH(CH₃)₂), C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl-Y¹—, heteroaryl-Y¹—,aryl-(O)_(t)-aryl-Y¹—, aryl-(O)_(t)-heteroaryl-Y¹— (particularly whereinaryl represents phenyl and heteroaryl represents tetrazolyl,oxadiazolyl, thiazolyl or oxazolyl), heteroaryl-(O)_(t)-aryl-Y¹—,heteroaryl-(O)_(t)-heteroaryl-Y¹— (particularly wherein heteroarylrepresents oxazolyl, thiazolyl, thiophenyl, pyrazolyl, pyrazinyl,furanyl, pyridinyl or tetrazolyl), C₂₋₆ alkenyl-Y¹—, aryl-O—Y¹—(particularly wherein aryl represents phenyl), heteroaryl-O—Y¹—, C₁₋₆alkyl-SO₂—Y¹— (particularly wherein C₁₋₆ alkyl represents methyl),M-Y¹—, —CN, J²-Y¹— or C₃₋₈ cycloalkyl-Y¹— (particularly cyclopropyl andcyclohexyl) or C₃₋₈ cycloalkenyl-Y¹—, which cycloalkyl or cycloalkenylmay be optionally substituted by one or more hydroxyl or C₁₋₆ alkylgroups.

Particularly, R¹ represents C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl-Y¹—, heteroaryl-Y¹—, aryl-(O)_(t)-aryl-Y¹—,aryl-(O)_(t)-heteroaryl-Y¹—, heteroaryl-(O)_(t)-aryl-Y¹—,heteroaryl-(O)_(t)-heteroaryl-Y¹—, C₂₋₆ alkenyl-Y¹—, aryl-O—Y¹—,heteroaryl-O—Y¹—, C₁₋₆ alkyl-SO₂—Y¹—, M-Y¹— or C₃₋₈ cycloalkyl-Y¹— orC₃₋₈ cycloalkenyl-Y¹—, which cycloalkyl or cycloalkenyl may beoptionally substituted by one or more hydroxyl or C₁₋₆ alkyl groups.

More preferably, R¹ represents aryl-Y¹—, aryl-O—Y¹—, heteroaryl-Y¹—,aryl-(O)_(t)-heteroaryl-Y¹— or heteroaryl-(O)_(t)-heteroaryl-Y¹—,especially aryl-Y¹—, heteroaryl-Y¹, heteroaryl-(O)_(t)-heteroaryl-Y¹— oraryl-(O)_(t)-heteroaryl-Y¹—. In this definition, aryl preferablyrepresents phenyl optionally substituted by one or more —SO₂—N(CH₃)₂,—SO₂CH₃, halogen (especially fluorine or chlorine), C₁₋₆ alkyl(especially methyl), CH₃CONH—, —CF₃, CH₃O—, —CONH₂, (CH₃)₂N— or —SCH₃groups. Further preferred phenyl substituents include —NHSO₂CH₃, —COOH,—COOCH₃ and —CONH-cyclopropyl. Yet further preferred phenyl substituentsinclude —SO₂NHcyclopropyl, —SO₂NHCH₂CH₃, —SO₂NHCH₃, —N(CH₃)SO₂CH₃,N(SO₂CH₃)₂, —NHCOCH₂N(CH₃)₂, —NHCOCH(CH₃)₂, —NH₂, —SO₂NH₂, —NHCONHCH₃,—NO₂, —CONH(CH₂)₂OCH₃, —CONHCH(CH₃)₂, —CONH(CH₂)₂OH, —CONH(CH₂)₂N(CH₃)₂,—CON(CH₃)₂, —CONHCH₂CH₃, —CONHCH₃, —COCH₃, —COCH(CH₃)₂, —CN, —OH,—CO-4-methyl-1-piperazinyl and —COmorpholinyl. Heteroaryl preferablyrepresents indolyl, thiophenyl, oxazolyl, pyrazolyl, thiazolyl,pyrimidinyl or furanyl optionally substituted with one or more C₁₋₆alkyl (especially methyl), CH₃O— or halogen (especially bromine) groups.Heteroaryl also preferably represents tetrazolyl or pyrazinyl. Furtherpreferred groups which heteroaryl may represent include benzotriazolyl,pyrrolopyridine, benzothiazolyl, pyridinyl, quinoxalinyl and imidazolyl.Suitable heteroaryl substituents include halogen (especially bromine),—COCH₃, —COOCH₃, —CH₃, —CH(CH₃)₂, morpholinyl, cyclopropyl, —CH₂CH(CH₃)₂and —CH═C(CH₃)₂.

A most particularly preferred group of compounds are those in which R¹is aryl-(O)_(t)-heteroaryl-Y¹— especially wherein heteroaryl representsoptionally substituted oxazolyl, (especially oxazolyl substituted bymethyl), aryl represents phenyl and t represents 0.

Especially preferred R¹ is aryl-Y¹—, particularly when aryl representsphenyl optionally substituted by any of the above substituents, mostespecially phenyl substituted by —SO₂NH₂.

Preferably, Y¹ represents a bond, C₁₋₆ alkylene, C₃₋₈ cycloalkyl or—CHCH₃, particularly C₁₋₆ alkylene or C₃₋₈ cycloalkyl, most preferablymethylene, ethylene or cyclopropyl, especially methylene or cyclopropyl,most especially methylene.

Preferably, R² represents hydrogen.

Preferably, X represents methylene.

Preferably, R³ and R⁴ independently represent hydrogen or methyl,especially hydrogen.

Preferably, Z represents a bond, CO, CR⁹R⁶(CH₂)_(n), CHR⁶(CH₂)_(n)O,CHR⁶(CH₂)_(n)S, CHR⁶(CH₂)_(n)OCO or CHR⁶(CH₂)_(n)CO.

More preferably, Z represents a bond, CO, CHR⁶(CH₂)_(n), CHR⁶(CH₂)_(n)O(particularly (CH₂)₂O) or CHR⁶(CH₂)_(n)CO, more particularlyCHR⁶(CH₂)_(n) or CHR⁶(CH₂)_(n)CO, most preferably CH₂, (CH₂)₃, CHCH₃orCH₂CO, especially CH₂ or CH₂CO, most especially CH₂.

Preferably, R⁵ represents C₂₋₆ alkenyl (particularly —CH₂CH(CH₃)═CH₂),aryl, heteroaryl or a group of formula —Y²-J¹, more preferably aryl,heteroaryl or a group of formula —Y²-J¹, most preferably monocyclicaryl, heteroaryl or a group of formula —Y²-J¹, especially aryl or—Y²-J¹, particularly phenyl which may be optionally substituted. We alsoespecially prefer R⁵ to represent heteroaryl, particularly thiophenylwhich may be optionally substituted. Other groups which heteroarylpreferably represents include benzoxadiazolyl, benzothiadiazolyl orbenzothiophenyl which may be optionally substituted. We mostparticularly prefer R⁵ to represent phenyl optionally substituted by oneor more (eg. 1, 2 or 3) halogen groups. Other preferred substituents forphenyl include —CN and —CF₃. We also most particularly prefer R⁵ torepresent thiophenyl optionally substituted by one or more (eg. 1, 2 or3) halogen groups.

Especially preferred R⁵ groups are dichlorophenyl, difluorophenyl,fluorophenyl, chlorothiophenyl, chlorophenyl and trifluorophenyl, mostespecially dichlorophenyl, difluorophenyl, fluorophenyl andchlorothiophenyl.

Most preferred R⁵ is dichlorophenyl (particularly 3,4-dichlorophenyl,2,3-dichlorophenyl and 2,5-dichlorophenyl), 4-fluorophenyl and3,4-difluorophenyl.

Most especially preferred R⁵ is dichlorophenyl, particularly3,4-dichlorophenyl.

Preferably, y² represents a bond.

Preferably, J¹ represents indolinyl, particularly indolin-1-yl.

Preferably, J² represents optionally substituted piperidinyl(particularly piperidinyl substituted by —COOC₁₋₆alkyl eg. —COOC(CH₃)₃)or thiomorpholinyl (particularly dioxidothiomorpholinyl) ordioxidothiomorpholinyl.

Preferably, Y³ represents a bond.

Preferably, R³ represents hydrogen.

Preferably, R⁷ and R⁸ represent hydrogen.

Preferably, R⁹ represents hydrogen.

Preferably, R¹⁰ and R¹³ independently represent hydrogen or methyl,especially hydrogen.

Preferably, R¹¹ and R¹² independently represent hydrogen or methyl orR¹¹ and R¹² together with the nitrogen atom to which they are attachedmay form a morpholine, piperidine or pyrrolidine ring, especiallyhydrogen or methyl.

Preferably, R¹⁴ and R¹⁵ independently represent hydrogen or methyl.

Preferably, R¹⁶ and R¹⁷ independently represent hydrogen, methyl, ethyl,isopropyl, 2-hydroxyethyl, 2-methoxyethyl, cyclopropyl or2-(dimethylamino)ethyl. Most preferably, R¹⁶ and R¹⁷ independentlyrepresent hydrogen or cyclopropyl.

Preferably, R^(c) and R^(d) independently represents hydrogen or methyl,most preferably hydrogen or R^(c) and R^(d) together with the carbonatom to which they are attached preferably forms cyclopropyl.

Preferably, R^(e) and R^(f) both represent hydrogen.

Preferably, a and b both represent 1.

Preferably, n represents 0, 1 or 2, more preferably 0.

Preferably, p and q independently represent 0 or 1 such that p+qrepresent 0-1. Most preferably, p and q both represent 0.

Preferably, t represents 0.

Preferably, W represents pyrrolidinyl or piperidinyl, especiallypyrrolidinyl.

Preferably, X¹ represents sulphur, oxygen or NR¹¹. More preferably, X¹represents oxygen or NR¹¹.

Preferably, X² represents CH₂, oxygen or NR¹².

Preferably, m¹ and m² independently represent an integer from 1 to 2,such that m¹+m² is in the range from 3 to 4.

Suitable salts of the compounds of formula (I) include physiologicallyacceptable salts and salts which may not be physiologically acceptablebut may be useful in the preparation of compounds of formula (I) andphysiologically acceptable salts thereof. If appropriate, acid additionsalts may be derived from inorganic or organic acids, for examplehydrochlorides, hydrobromides, sulphates, phosphates, acetates,benzoates, citrates, succinates, lactates, tartrates, fumarates,maleates, 1-hydroxy-2-naphthoates, palmoates, methanesulphonates,formates or trifluoroacetates. Examples of solvates include hydrates.

When compounds of formula (I) contain chiral centres, the inventionextends to mixtures of enantiomers (including racemic mixtures) anddiastereoisomers as well as to individual enantiomers. Generally it ispreferred to use a compound of formula (I) in the form of a singleenantiomer.

The compounds of formula (I) and salts and solvates thereof may beprepared by the methodology described hereinafter, constituting afurther aspect of this invention.

A process according to the invention for preparing a compound of formula(I) which comprises:

-   (a) acylation of a compound of formula (II)    or a protected derivative thereof wherein R², R³, R⁴, R⁵, X, Z, a    and b are as described above, with a compound of formula R¹COOH or    an activated derivative thereof, wherein R¹ is as described above;    or-   (b) reacting a compound of formula (III)    or a protected derivative thereof wherein R¹, R², R³, R⁴, X, a and b    are as defined above, with a compound of formula-   L¹-Z-R⁵, wherein Z and R⁵ are as defined above and L¹ represents a    suitable leaving group; or-   (c) deprotecting a compound of formula (I) which is protected; or-   (d) interconversion of other compounds of formula (I).

We also provide a further process according to the invention forpreparing a compound of formula (I) which comprises:

-   (e) forming a compound of formula (I) wherein R¹ represents    heteroaryl-Y¹—, aryl-(O)_(t)-heteroaryl-Y¹— or    heteroaryl-(O)_(t)-heteroaryl-Y¹— (wherein said Y¹ group is attached    to heteroaryl via a heterocyclic nitrogen atom) and R² represents    hydrogen which comprises reacting a compound of formula (IV)    or a protected derivative thereof wherein R³, R⁴, R⁵, X, Y¹, Z, a    and b are as defined above, L² represents a suitable leaving group,    such as a halogen atom eg. bromine and P¹ represents a solid phase    resin bound protecting group, such as one described for process (c),    with a heterocyclic compound defined by the R¹ groups heteroaryl,    aryl-(O)_(t)-heteroaryl or heteroaryl-(O)_(t)-heteroaryl above    wherein said heteroaryl group contains at least one NH atom,    followed by removal of the solid phase resin bound protecting group;    or-   (f) forming a compound of formula (I) wherein Z represents    CR⁹R⁶(CH₂)_(n) and R⁹ represents hydrogen which comprises reacting a    compound of formula (III) or a protected derivative thereof with a    compound of formula R⁶CO(CH₂)_(n)R⁵, followed by reduction of the    resultant imine; or-   (g) forming a compound of formula (I) wherein Z represents CO by    reacting a compound of formula (III) or a protected derivative    thereof with a compound of formula R⁵COOH or an activated derivative    thereof.

Process (a) may be effected simply by the reaction of a compound offormula (II) with R¹COOH which may typically be achieved using an oveneg. a microwave oven at a power of 600W for 4 minutes. Examples ofactivated derivatives of R¹COOH which may be employed in this reactioninclude acid halides and anhydride derivatives (eg. the acid chloride).Alternatively, process (a) may be performed in the presence ofO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylammoniumhexafluorophosphate (HATU) and a suitable base, eg.N,N-diisopropylethylamine in a suitable solvent, eg.N,N-dimethylformamide at a suitable temperature, eg. room temperature.Process (a) may also be performed in the presence of1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride in the presence of a suitable base, eg.N,N-diisopropylethylamine and a suitable solvent, eg. dichloromethane orN,N-dimethylformamide, at a suitable temperature, eg. room temperature.Further, process (a) may be performed in the presence of1,1′-carbonyldiimidazole in the presence of a suitable solvent, eg.N,N-dimethylformamide at a suitable temperature, eg. room temperature.Process (a) may also be performed in the presence of a suitable basesuch as polyvinylpyridine and a suitable solvent, such asdichloromethane at a suitable temperature such as room temperature.

Process (b) may be performed in the presence of a suitable solvent eg.N,N-dimethylformamide, optionally in the presence ofN,N-diisopropylethylamine at a suitable temperature eg. roomtemperature. Examples of suitable leaving groups (L¹) include halogen,eg. chlorine.

In process (c), examples of protecting groups and the means for theirremoval can be found in T. W. Greene and P. G. M. Wuts ‘ProtectiveGroups in Organic Synthesis’ (J. Wiley and Sons, 3rd Ed. 1999). Suitableamine protecting groups include sulphonyl (e.g. tosyl), acyl (e.g.benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (e.g. benzyl),which may be removed by hydrolysis or hydrogenolysis as appropriate.Other suitable amine protecting groups include trifluoroacetyl (—COCF₃)which may be removed by base catalysed hydrolysis, or a solid phaseresin bound benzyl group, such as a Merrifield resin bound2,6-dimethoxybenzyl group (Ellman linker) or a2,6-dimethoxy4-[2-(polystyrylmethoxy)ethoxy]benzyl, which may be removedby acid catalysed hydrolysis, for example with trifluoroacetic acid.

Process (d) may be performed using conventional interconversionprocedures such as epimerisation, oxidation, reduction, alkylation,nucleophilic aromatic substitution, ester hydrolysis or amide bondformation. Alternative conditions for process (d) includet-butoxycarbonyl group addition or removal and sulphonylation.

Process (e) may be performed using a suitable base, eg. potassiumtert-butoxide and a suitable solvent, eg. N,N-dimethylformamide, at asuitable temperature, eg. 60° C.

Process (f) may be performed in the presence of a suitable acid eg.acetic acid and a suitable reducing agent, eg. sodiumtriacetoxyborohydride in a suitable solvent, eg. dichloromethane at asuitable temperature, eg. room temperature.

Process (g) may be performed in the presence of suitable reagents, eg.1,-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride and1-hydroxybenzotriazole in the presence of a suitable base, eg.N,N-diisopropylethylamine and a suitable solvent eg.N,N-dimethylformamide at a suitable temperature, eg. room temperature.

Compounds of formula (II) may be prepared according to the followingprocess:

wherein R², R³, R⁴, R⁵, X, a, b and Z are as defined above and L¹represents a suitable leaving group eg. chlorine and P² represents asuitable protecting group eg. one mentioned above, such as —COCF₃. Step(i) comprises the use of a suitable solvent eg. N,N-dimethylformamide inthe presence of suitable reagents eg. sodium iodide and potassiumcarbonate at a suitable temperature eg. room temperature. Alternativelystep (i) may comprise the use of a suitable solvent eg.N,N-dimethylformamide, in the presence of a suitable base such asN,N-diisopropylethylamine at a suitable temperature eg. roomtemperature. Step (ii) comprises deprotection under conventionalconditions appropriate for the protecting groups. When P² represents—COCF₃, deprotection may be achieved by the use of water and methanol inthe presence of potassium carbonate at room temperature.

Compounds of formula (II)^(P) may also be prepared by reductiveamination of compounds of formula (V) in an analogous manner to thatdescribed in process (f) above.

Compounds of formula (II) wherein R² represents hydrogen, X representsmethylene, a and b represent 1 and R³ and R⁴ are both attached to themorpholine ring at the 5-position may be prepared according to thefollowing process:

wherein R³, R⁴ and R⁵ and Z are as defined above and L¹ represents asuitable leaving group eg. chlorine. Step (i) comprises heating in theabsence of solvent at between 50 and 60° C. Step (ii) comprises heatingwith 2-(oxiran-2-ylmethyl)-1H-isoindole-1,3(2H)-dione at 80° C. undernitrogen, followed by stirring with concentrated sulphuric acid at 150°C.

Compounds of formula (II) wherein R² represents H may be preparedaccording to the following process:

wherein R³, R⁴, R⁵, X, a, b and Z are as defined above and L¹ representsa suitable leaving group eg. chlorine. Step (i) comprises heating acompound of formula (III; Merrifield Resin) with sodium carbonate in asuitable solvent eg. dimethylsulphoxide at a suitable temperature eg.150° C. Step (ii) comprises reacting a compound of formula (IX) with acompound of formula (X) in the presence of a suitable solvent eg.tetrahydrofuran at a suitable temperature eg. room temperature. Step(iii) comprises the use of suitable solvent eg. N,N-dimethylformamideand a suitable base eg. N,N-diisopropylethylamine at a suitabletemperature eg. 70° C., followed by deprotection under conventionalconditions appropriate for the Merrifield resin protecting group eg.acid catalysed hydrolysis.

Compounds of formula R¹COOH used in process (a) above (and activatedderivatives thereof) are either known compounds or may be synthesised byknown methods.

For example, compounds of formula R¹COOH wherein R¹ representsheteroaryl-Y¹, aryl-(O)_(t)-heteroaryl-Y¹— orheteroaryl-(O)_(t)-heteroaryl-Y¹— (wherein the heteroaryl moiety linkedto Y¹ represents 1,3-oxazol-4-yl and t represents 0) may be preparedaccording to the following process:

wherein R^(w) represents a suitable substituent described above for aheteroaryl group, especially C₁₋₆ alkyl, R^(x) represents C₁₋₆ alkyl,aryl or heteroaryl, R^(z) represents C₁₋₆ alkyl, especially ethyl, Halrepresents a halogen atom, especially bromine and Y¹ is as definedabove.

Compounds of formula (XII) may be prepared by following the proceduredescribed in Svendsen and Boll (1973) Tetrahedron 29, 4251-4258.

Step (i) may typically be performed in the presence of a suitablesolvent, eg. toluene at a suitable temperature eg. at 140° C. and usingsuitable conditions, eg. Dean-Stark conditions.

Step (ii) may typically be performed in the presence of a suitablealkali, eg. sodium hydroxide and suitable solvents, eg. water andethanol at a suitable temperature, eg. 70° C.

Compounds of formula R¹COOH wherein R¹ represents heteroaryl-Y¹,aryl-(O)_(t)-heteroaryl-Y¹— or heteroaryl-(O)_(t)-heteroaryl-Y¹—(wherein the heteroaryl moiety linked to Y¹ represents 1,3-oxazol-4-yland t represents 0) may also be prepared according to the followingprocess:

wherein R^(v) represents C₁₋₆ alkyl, especially methyl, R^(w) representsa suitable substituent described above for a heteroaryl group,especially C₁₋₆ alkyl, R^(x) represents C₁₋₆ alkyl, aryl or heteroaryl,Hal represents a halogen atom, especially chlorine and Y¹ is as definedabove.

Step (i) may typically be performed in the presence of a suitable base,eg. pyridine, at a suitable temperature, eg. from 0° C. to roomtemperature.

Step (ii) may typically be performed in the presence of a suitable base,eg. pyridine at a suitable temperature, eg. 90° C., followed by theaddition of water at a suitable temperature, eg. 90° C.

Step (iii) may typically be performed in the presence of a suitablereagent, eg. phosphorus oxychloride and a suitable solvent, eg. toluene,under suitable conditions, eg. 110° C.

Step (iv) may typically be performed in the presence of a suitablealkali eg. 2M aqueous sodium hydroxide, and a suitable solvent, eg.ethanol at a suitable temperature, eg. room temperature.

Compounds of formula (III) as the R-isomer, wherein R² representshydrogen, X represents methylene, a and b represent 1 and R³ and R⁴ bothrepresent hydrogen may be prepared according to the following process:

wherein R¹ is as defined above and P³ is a suitable protecting group,eg. benzyl.

Compounds of formula (XXII) may be prepared as described in EP0995746.

Step (i) typically comprises the use of 1-hydroxybenzotriazole and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in thepresence of a suitable base, eg. N,N-diisopropylethylamine and asuitable solvent, eg. N,N-dimethylformamide, at a suitable temperature,eg. room temperature.

Step (ii) typically comprises a simple deprotection reaction, eg. whichmay comprise the use of 10% palladium on activated carbon in thepresence of ammonium formate and a suitable solvent, eg. ethanol.

Compounds of formula (III) as the S-isomer, wherein R¹ is as definedabove, may be prepared by an analogous process.

Compounds of formula (IV) may be prepared according to the followingprocess:

wherein R³, R⁴, R⁵, X, Y¹, Z, a and b are as defined above, L²represents a suitable leaving group, such as a halogen atom, eg. bromineand P¹ represents a solid phase resin bound protecting group, such asone described in process (c).

Step (i) typically comprises the use of a suitable reagent, eg.1,3-diisopropylcarbodiimide in the presence of one or more suitablesolvents, eg. dichloromethane and N,N-dimethylformamide.

Compounds of formula (V), (I), (VIII), (X), (XII), (XIII), (XVI),(XVII), (XIX) and (XXII) are either known or may be prepared inaccordance with known procedures.

Compounds of formula L¹-Z-R⁵, R⁶CO(CH₂)_(n)R⁵, R⁵COOH, L²-Y¹—COOH andheterocyclic compounds defined by the R¹ groups heteroaryl,aryl-(O)_(t)-heteroaryl or heteroaryl-(O)_(t)-heteroaryl above are alsoeither known or may be prepared in accordance with known procedures.

Compounds of formula (III) may be prepared in accordance with processesanalogous to those described above for compounds of formula (I),employing suitable protection for the morpholine (or analogue) NH, e.g.t-butoxycarbonyl protection.

Compounds of formula (II), (III) and (IV) in their protected anddeprotected form and salts and solvates thereof are also claimed as anaspect of the invention.

Compounds of the invention may be tested for in vitro and in vivobiological activity in accordance with the following assays.

(a) CCR-3 Binding Assay

A CCR-3 competition binding SPA (scintillation proximity assay) was usedto assess the affinity of novel compounds for CCR-3. Membranes preparedfrom K562 cells stably expressing CCR-3 (2.5 μg/well) were mixed with0.25 mg/well wheat-germ agglutinin SPA beads (Amersham) and incubated inbinding buffer (HEPES 50 mM, CaCl₂ 1 mM, MgCl₂ 5 mM, 0.5% BSA) at 4° C.for 1.5 hr. Following incubation, 20 pM of [¹²⁵I] eotaxin (Amersham) andincreasing concentrations of compound (1 pM to 30 μM) were added andincubated in a 96 well plate for 2 hr at 22° C. then counted on aMicrobeta plate counter. The total assay volume was 100 μl. Competitionbinding data were analysed by fitting the data with a four parameterlogistic equation. Data are presented as the mean pIC₅₀ values (negativelogarithm of the concentration of compound which inhibits [¹²⁵I]eotaxinbinding by 50%) from at least two experiments.

(b) Eosinophil Chemotaxis Assay.

Compounds were evaluated for their inhibitory effect on eosinophilchemotaxis. Eosinophils were purified from human peripheral blood bystandard CD16 cell depletion using a Miltenyi cell separation column anda magnetic Super Macs magnet as previously described (Motegi & Kita,1998; J. Immunology. 161:4340-6). Cells were re-suspended in RPMI1640/10% FCS solution and incubated with calcein-AM (Molecular Probes)at 37° C. for 30 mins. Following incubation, the eosinophils werecentrifuged at 400 g for 5 min and re-suspended in RPMI/FCS at 2.2million/ml. Cells. were then incubated in the presence of increasingconcentration of compounds (1 pM to 30 μM) at 37° C. for 30 mins. Forcontrol responses cells were incubated with RPMI/FCS only. The agonisteotaxin (either a concentration response curve or for the functionalinhibition curves an EC₈₀ concentration) was added to the lower chamberof a 96 well chemotaxis plate (5 μm filter Receptor Technologies).Eosinophils (50 μl of 2 million/ml cells) were added to the top chamberof the filter plate and incubated at 37° C. for 45 mins. Cells remainingon top of the chemotaxis filter were removed and the number ofeosinophils which had migrated were quantified by reading the plate on afluorescent plate reader. Inhibiton curves for the effect of compoundson eosinophil chemotaxis were analysed by fitting the data with a fourparameter logistic equation. Functional pK_(i) values (fpK_(i)) weregenerated using the equation below (Lazareno & Birdsall, 1995. Br. J.Pharmacol 109: 1110-9).${fpKi} = \frac{{IC}_{50}}{1 + \left\lbrack \frac{\lbrack{Agonist}\rbrack}{{EC}_{50}} \right\rbrack}$(c) Guinea-Pig Ovalbumin ModelInhibition of Eosinophil Infiltration and Hyper-Reactivity in the GuineaPig

In a method based on that described by Danahay et al., 1997, ovalbuminsensitised guinea pigs were dosed with mepyramine (30 mg kg⁻¹ ip) toprotect against anaphylactic bronchospasm. Test compounds, dissolved in10% DMSO and 90% PEG200, were given by the oral route, 30 minutes beforeovalbumin challenge (10 minutes breathing of an aerosol generated from a0.5% solution of ovalbumin). Hyper-reactivity of the airways to thethromboxane mimetic U46619, was measured 24 hours after ovalbuminchallenge in un-restrained animals using a whole body plethysmograph(Buxco Ltd., USA). The guinea pigs were then sacrificed and the lungslavaged. Total and differential leukocyte counts were then obtained forthe bronchoalveolar lavage fluid and the percentage reduction ineosinophil accumulation determined (Sanjar et al., 1992). Data waspresented as the inhibitory effect of the specified dose expressed as apercentage of the vehicle control response.

Examples of disease states in which the compounds of the invention havepotentially beneficial anti-inflammatory effects include diseases of therespiratory tract such as bronchitis (including chronic bronchitis),asthma (including allergen-induced asthmatic reactions), chronicobstructive pulmonary disease (COPD) and rhinitis. Another disease ofthe respiratory tract in which the compounds of the invention havepotentially beneficial effects is sinusitis. Other relevant diseasestates include diseases of the gastrointestinal tract such as intestinalinflammatory diseases including inflammatory bowel disease (e.g. Crohn'sdisease or ulcerative colitis) and intestinal inflammatory diseasessecondary to radiation exposure or allergen exposure. Furthermore,compounds of the invention may be used to treat nephritis, skin diseasessuch as psoriasis, eczema, allergic dermatitis and hypersensitivityreactions and diseases of the central nervous system which have aninflammatory component eg. Alzheimer's disease, meningitis, multiplesclerosis and AIDS dementia. Compounds of the present invention may alsobe of use in the treatment of nasal polyposis, conjunctivitis orpruritis. Additionally, the compounds of the present invention may be ofuse in the treatment of viral diseases such as HIV.

Further examples of disease states in which compounds of the inventionhave potentially beneficial effects include cardiovascular conditionssuch as atherosclerosis, peripheral vascular disease and idiopathichypereosinophilic syndrome. Other diseases for which the compounds ofthe present invention may be beneficial are other hypereosinophilicdiseases such as Churg-strauss syndrome. Additionally, eosinophilia iscommonly found in parasitic diseases, especially helminth infections,and thus the compounds of the present invention may be useful intreating inflammation arising from hyper-eosinophilic states of diseasessuch as hydatid cyst (Echinococcus sp.), tapeworm infections (Taeniasp.), blood flukes (schistosomiasis), and nematode (round worms)infections such as:—Hookworm (Ancylostoma sp.), Ascaris, Strongyloides,Trichinella, and particularly lymphatic filariasis including Onchocerca,Brugia, Wucheria (Elephantiasis).

Compounds of the invention may be useful as immunosuppressive agents andso have use in the treatment of auto-immune diseases such as allografttissue rejection after transplantation, rheumatoid arthritis anddiabetes.

Compounds of the invention may also be useful in inhibiting metastasis.

Diseases of principal interest include asthma, COPD and inflammatorydiseases of the upper respiratory tract involving seasonal and perennialrhinitis. Preferred diseases of principle interest include asthma andinflammatory diseases of the upper respiratory tract involving seasonaland perennial rhinitis. Further diseases also of principle interestinclude inflammatory diseases of the gastrointestinal tract such asinflammatory bowel disease.

It will be appreciated by those skilled in the art that reference hereinto treatment extends to prophylaxis as well as the treatment ofestablished conditions.

As mentioned above, compounds of formula (I) are useful aspharmaceuticals, in particular as anti-inflammatory agents.

There is thus provided as a further aspect of the invention a compoundof formula (I) or a physiologically acceptable salt or solvate thereoffor use as pharmaceuticals, particularly in the treatment of patientswith inflammatory conditions, eg. asthma or rhinitis.

According to another aspect of the invention, there is provided the useof a compound of formula (I) or a physiologically acceptable salt orsolvate thereof for the manufacture of a medicament for the treatment ofpatients with inflammatory conditions, eg. asthma or rhinitis.

In a further or alternative aspect there is provided a method for thetreatment of a human or animal subject with an inflammatory conditioneg. asthma or rhinitis, which method comprises administering to saidhuman or animal subject an effective amount of a compound of formula (I)or a physiologically acceptable salt or solvate thereof.

The compounds according to the invention may be formulated foradministration in any convenient way, and the invention therefore alsoincludes within its scope pharmaceutical compositions for use inanti-inflammatory therapy, comprising a compound of formula (I) or aphysiologically acceptable salt or solvate thereof together, ifdesirable, with one or more physiologically acceptable diluents orcarriers. There is also provided a process for preparing such apharmaceutical formulation which comprises mixing the ingredients.

The compounds according to the invention may, for example, be formulatedfor oral, inhaled, intranasal, buccal, parenteral or rectaladministration, preferably for oral administration.

Tablets and capsules for oral administration may contain conventionalexcipients such as binding agents, for example syrup, acacia, gelatin,sorbitol, tragacanth, mucilage of starch, cellulose or polyvinylpyrrolidone; fillers, for example, lactose, microcrystalline cellulose,sugar, maize-starch, calcium phosphate or sorbitol; lubricants, forexample, magnesium stearate, stearic acid, talc, polyethylene glycol orsilica; disintegrants, for example, potato starch, croscarmellose sodiumor sodium starch glycollate; or wetting agents such as sodium laurylsulphate. The tablets may be coated according to methods well known inthe art. Oral liquid preparations may be in the form of, for example,aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, ormay be presented as a dry product for constitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example, sorbitolsyrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxymethylcellulose, carboxymethyl cellulose, aluminium stearate gel orhydrogenated edible fats; emulsifying agents, for example, lecithin,sorbitan mono-oleate or acacia; non-aqueous vehicles (which may includeedible oils), for example almond oil, fractionated coconut oil, oilyesters, propylene glycol or ethyl alcohol; or preservatives, forexample, methyl or propyl p-hydroxybenzoates or sorbic acid. Thepreparations may also contain buffer salts, flavouring, colouring and/orsweetening agents (e.g. mannitol) as appropriate.

For buccal administration the compositions may take the form of tabletsor lozenges formulated in conventional manner.

The compounds may also be formulated as suppositories, e.g. containingconventional suppository bases such as cocoa butter or other glycerides.

The compounds according to the invention may also be formulated forparenteral administration by bolus injection or continuous infusion andmay be presented in unit dose form, for instance as ampoules, vials,small volume infusions or pre-filled syringes, or in multi-dosecontainers with an added preservative. The compositions may take suchforms as solutions, suspensions, or emulsions in aqueous or non-aqueousvehicles, and may contain formulatory agents such as anti-oxidants,buffers, antimicrobial agents and/or tonicity adjusting agents.Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g. sterile, pyrogen-free water,before use. The dry solid presentation may be prepared by filling asterile powder aseptically into individual sterile containers or byfilling a sterile solution aseptically into each container andfreeze-drying.

The pharmaceutical compositions according to the invention may also beused in combination with other therapeutic agents, for exampleanti-inflammatory agents (such as corticosteroids (e.g. fluticasonepropionate, beclomethasone dipropionate, mometasone furoate,triamcinolone acetonide or budesonide) or NSAIDs (eg. sodiumcromoglycate, nedocromil sodium, PDE-4 inhibitors, leukotrieneantagonists, iNOS inhibitors, tryptase and elastase inhibitors, beta-2integrin antagonists and adenosine 2a agonists)) or beta adrenergicagents (such as salmeterol, salbutamol, formoterol, fenoterol orterbutaline and salts thereof), anti-histamines (eg methapyrilene orloratadine) or antiinfective agents (eg. antibiotics, antivirals).

It will be appreciated that when the compounds of the present inventionare administered in combination with other therapeutic agents normallyadministered by the inhaled or intranasal route, that the resultantpharmaceutical composition may be administered by the inhaled orintranasal route.

Compounds of the invention may conveniently be administered in amountsof, for example, 0.001 to 500 mg/kg body weight, preferably 0.01 to 500mg/kg body weight, more preferably 0.01 to 100 mg/kg body weight, 1 to 4times daily. The precise dose will of course depend on the age andcondition of the patient and the particular route of administrationchosen.

The compounds of the invention have the advantage that they may be moreefficacious, show greater selectivity, have fewer side effects, have alonger duration of action, be more bioavailable when administered by theoral route, have more ready and economic synthesis, or have other moredesirable properties than similar known compounds.

The invention may be illustrated by reference to the following examples:

EXAMPLES

General Experimental Details

Standard Automated Preparative HPLC Column, Conditions and Eluent

Automated preparative high performance liquid chromatography (autoprep.HPLC) was carried out using a Supelco+5 μm (100 mm×22 mm internaldiameter) column eluted with a mixture of solvents consisting of i) 0.1%trifluoroacetic acid in water and ii) 0.1% trifluoroacetic acid inacetonitrile, the eluent being expressed as the percentage of ii) in thesolvent mixture, at a flow rate of 4 ml per minute.

Mass Directed Automated Preparative HPLC Column, Conditions and Eluent

Mass directed automated preparative high performance liquidchromatography was carried out using an LCABZ+5 μm (5 cm×10 mm internaldiameter) column, employing gradient elution using two solvent systems,(A) 0.1% formic acid in water, and (B) 95% acetonitrile and 0.5% formicacid in water, at a flow rate of 8ml min¹. Mass spectrometry was carriedout using a VG Plafform Mass Spectrometer, with an HPI 100 Diode ArrayDetector and Accurate Flow Splitter.

Normal Phase Automated Preparative HPLC Column—Conditions

Normal phase automated preparative high performance liquidchromatography (normal phase autoprep HPLC) was carried out using aNucleosil silica 5 μm (100 mm×20 mm internal diameter) column elutedwith an ethyl acetate:heptane two-step gradient (i) 0% to 25% ethylacetate over 7min followed by (ii) 25% to 100% ethyl acetate over5.5min; at a flow rate of 30mlImin.

LC/MS System

Three alternative Liquid Chromatography Mass Spectroscopy (LC/MS)Systems were used:

System A

This system used a 3 μm ABZ+PLUS (3.3 cm×4.6 mm internal diameter)column, eluting with solvents: A—0.1%v/v formic acid+0.077% w/v ammoniumacetate in water; and B—95:5 acetonitrile:water+0.05%vlv formic acid, ata flow rate of 3 ml per minute. The following gradient protocol wasused: 100% A for 0.7 mins; A+B mixtures, gradient profile 0-100% B over3.5 mins; hold at 100% B for 1.1 mins; return to 100% A over 0.2 mins.

System B

This system used a 3 μm ABZ+PLUS (3.3 cm×4.6 mm internal diameter)column, eluting with solvents: A—0.1%v/v formic acid+0.077% w/v ammoniumacetate in water; and B—95:5 acetonitrile:water+0.05% v/v formic acid,at a flow rate of 1 ml per minute. The following gradient protocol wasused: 100% A for 1.0 min; A+B mixtures, gradient profile 0-100% B over9.0 mins; hold at 100% B for 3.0 mins; return to 100% A over 2.0 mins.

System C

This system used a 3 μm ABZ+PLUS (3.3 cm×4.6 mm internal diameter)column, eluting with solvents: A—0.1%v/v formic acid+0.077% wlv ammoniumacetate in water; and B—95:5 acetonitrile:water+0.05%vlv formic acid, ata flow rate of 1 ml per minute. The following gradient protocol wasused: 100% A for 2.0 mins; A+B mixtures, gradient profile 0-100% B over20 mins; hold at 100% B for 5.0 mins; return to 100% A over 2.0 mins;hold at 100% A for 1.0 mins.

All LC/IMS systems (apart from the Mass Directed Automated PreparativeHPLC system) used a micromass spectrometer, with electrospray ionisationmode, positive and negative ion switching, mass range 80-1000 a.m.u.

Thermospray Mass Spectra

Thermospray Mass Spectra were determined on a HP 5989A engine massspectrometer, +ve thermospray, source temperature 250° C., probetemperatures 120° C. (stem), 190° C. (tip), detection mass range 100-850a.m.u. Compounds were injected in 10 μl of a mixture of solventscomprising 65% methanol and 35% 0.05M aqueous ammonium acetate, at aflow rate of 0.7 ml/min.

Normal Phase Analytical HPLC Method

Normal phase automated analytical high performance liquid chromatography(normal phase analytical HPLC) was carried out using a Nucleosil silica3 μm (150 mm×4.6 mm internal diameter) column eluted with an ethylacetate:heptane two-step gradient (i) 0% to 40% ethyl acetate over 7 minfollowed by (ii) 40% to 100% ethyl acetate over 2.5 min; at a flow rateof 2 ml/min.

Standard Chiral Analytical HPLC System

This system used a 250×4.6 mm Chiralpak AD 10 μm column, eluting withabsolute ethanol:heptane mixtures at a flow rate of 1 ml per minute,with UV detection at 215 nm.

Standard Chiral Preparative HPLC System

This system used a Chiralpak AD column (2 cm×25 cm), eluting withabsolute ethanol:heptane mixtures (15 ml/min over 25 mins, UV detectionat 215 nm).

Solid Phase Extraction (Ion Exchange)

‘SCX’ refers to Isolute Flash SCX-2 sulphonic acid solid phaseextraction cartridges.

Organic/Aqueous Phase Separation with Hydrophobic Frits

‘Hydrophobic frit’ refers to a Whatman polypropylene filter tube fittedwith a PTFE frit, pore size 5.0 μm.

All temperatures are in ° C.

INTERMEDIATES Intermediate 1:[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methylamine

A mixture of 2-[(3,4-dichlorobenzyl)amino]ethanol (Chem Abs No.40172-06-3, 0.980 g) and2-(oxiran-2-ylmethyl)-1H-isoindole-1,3(2H)-dione (1.10 g) was heated at80° C. under nitrogen for 3 h. The resulting solid mass was treated withconcentrated sulphuric acid (1.5 ml) then stirred at 150° C. for 24 h.The mixture was treated with water (100 ml) then washed with ethylacetate (2×100 ml). The dark aqueous phase was basified to ˜pH 12 using5M aqueous sodium hydroxide, then extracted with ethyl acetate (2×100ml). The combined organic extracts were washed with water and brine,dried (Na₂SO₄) and concentrated under vacuum to give the title compoundas a brown oil (1.02 g).

LC-MS (System A): Rt 1.6 min.

Intermediate 1 (Alternative procedure):[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methylamine

To a stirred solution of Intermediate 42 (2.97 g) in methanol (15 ml)and water (5 ml) was added potassium carbonate (5.53 g). The mixture wasstirred at 22° C. for 18 h before the methanol was removed in vacuo.Water (25 ml) was added and the mixture extracted with ethyl acetate(3×30 ml). The combined organic phases were washed with water (5 ml) andsaturated aqueous sodium chloride solution (10 ml) before drying oversodium sulphate, filtering and evaporation of the solvent in vacuo togive a pale yellow oil. The oil was purified by Biotage flashchromatography on a 90 g silica cartridge eluting with 75:8:1dichloromethane/ethanol/0.880 ammonia solution. The required fractionswere combined and the solvent evaporated in vacuo to give the titlecompound as a colourless oil (1.85 g).

LC/MS (System A) R_(t) 1.77 min, Mass Spectrum m/z 275 [MH⁺].

Intermediate 1A: [4-(3,4Dichlorobenzyl)morpholin-2-yl]methylamine saltwith para-toluenesulphonic acid 1:1

A solution of 2-[(3,4-dichlorobenzyl)amino]ethanol (2.25 g) and2-chloroacrylonitrile (1.0 ml) in tetrahydrofuran (3 ml) was heated at40° C. for 66 h. The solvent was evaporated in vacuo to leave a gum. Theresidue was redissolved in tetrahydrofuran (20 ml) and cooled to 0-5° C.Potassium tert-butoxide (1.2 g) was added portionwise to this solutionover 10 min and the mixture was stirred at 0-5° C. for a further 45 min.The mixture was diluted with water (20 ml) and ethyl acetate (20 ml),the phases were separated and the organic phase was washed with 20% w/waqueous sodium chloride solution. The organic phase was dried oversodium sulfate and the solvent was evaporated in vacuo to leave a gum(2.75 g).

A portion of this gum (0.22 g) in tetrahydrofuran (1 ml) was treateddropwise with a 1M solution of borane.tetrahydrofuran complex intetrahydrofuran (2.44 ml) at 15-25° C. The mixture was stirred at 15-25°C. for 16 h, and methanol (3 ml) was added dropwise. The mixture wasstirred for a further 5 h and the solvent was evaporated in vacuo. Theresidue was redissolved in ethyl acetate (4 ml) and p-toluenesulfonicacid monohydrate (0.123 g) was added. The mixture was heated at 50° C.for 20 min, and the suspension was cooled to 15-25° C. and stirred for15 min. The mixture was filtered, washed with ethyl acetate and dried togive the title compound (0.123 g) as a white solid.

LC/MS (System A) R_(t) 1.75 min. Mass spectrum m/z 275/277 [MH⁺]

Intermediate 2: 2-[(3,4-Dichlorobenzyl)amino]-2-methylpropan-1-ol

3,4-Dichlorobenzyl chloride (3.95 g) was added to2-amino-2-methylpropan-1-ol (17.8 g) and the mixture was stirred at 60°C. under nitrogen for 2 h. Excess amine was removed by distillationunder vacuum and the residue was partitioned between saturated aqueoussodium bicarbonate (100 ml) and ethyl acetate (100 ml). The phases wereseparated, the organic layer was washed with water (4×100 ml) and brine(100 ml), dried (Na₂SO₄) and concentrated under vacuum to give the titlecompound as a white solid (4.7 g).

LC-MS (System A): Rt 2.07 min.

Intermediate 3:1-[4-(3,4-Dichlorobenzyl)-5,5-dimethylmorpholin-2-yl]methanamine

A mixture of Intermediate 2 (0.260 g) and2-(oxiran-2-ylmethyl)-1H-isoindole-1,3(2H)-dione (0.205 g) was heated at80° C. under nitrogen for 3 h. The mixture was treated with concentratedsulphuric acid (0.3 ml) then stirred at 150° C. for 18 h. The mixturewas treated with water (25 ml) then washed with ethyl acetate (2×25 ml).The dark aqueous phase was basified to ˜pH 11 using 5M aqueous sodiumhydroxide then extracted with ethyl acetate (2×25 ml). The combinedorganic extracts were washed with water and brine, dried (Na₂SO₄) andconcentrated under vacuum to give the title compound as a brown oil(0.225 g).

LC-MS (System A): Rt 1.92 min.

Intermediate 4: 2-[(3,4-Dichlorobenzyl)amino]propan-1-ol

3,4-Dichlorobenzyl chloride (0.988 g) was added to 2-amino-1-propanol(4.10 g) and the mixture was stirred at 50° C. under nitrogen for 2 h.The mixture was partitioned between saturated aqueous sodium bicarbonate(100 ml) and ethyl acetate (100 ml) and the phases were separated. Theorganic layer was washed with water (4×100 ml) and brine, dried (Na₂SO₄)then concentrated under vacuum to give the title compound as a whitesolid (0.935 g).

LC-MS (System A): Rt 2.13 min.

Intermediate 5:1-[(cis)-4-(3,4-Dichlorobenzyl)-5-methylmorpholin-2-yl]methanamine (2:1Mixture with Trans Isomer)

A mixture of Intermediate 4 (0.470 g) and2-(oxiran-2-ylmethyl)-1H-isoindole-1,3(2H)-dione (0.410 g) was heated at80° C. under nitrogen for 5 h. The mixture was treated with concentratedsulphuric acid (0.6 ml) then stirred at 150° C. for 42 h. The mixturewas treated with water (50 ml) then washed with ethyl acetate (2×50 ml).The dark aqueous phase was basified to ˜pH 11 using 5M aqueous sodiumhydroxide then extracted with ethyl acetate (2×50 ml). The combinedorganic extracts were washed with water and brine, dried (Na₂SO₄) andconcentrated under vacuum to give the title compound as a brown oil(0.42 g).

LC-MS (System A): Rt 1.74 min.

Intermediate 6: 2-{[3-(3,4-Dichlorophenyl)propyl]amino}ethanol

4-(3-Bromopropyl)-1,2-dichlorobenzene (Chem Abs No. 29648-26-8, 1.30 g)was added to ethanolamine (2.8 ml) and the mixture stirred at 60° C.under nitrogen for 2 h. The mixture was concentrated under vacuum at 80°C. and the residue was partitioned between saturated aqueous sodiumbicarbonate (100 ml) and ethyl acetate (100 ml). The phases wereseparated, the aqueous layer was re-extracted with ethyl acetate (100ml) and the combined organic extracts were washed with water (2×100 ml)and brine then dried (Na₂SO₄). The solution was concentrated undervacuum to give the title compound as a pale yellow liquid (1.10 g).

LC-MS (System A): Rt 2.40 min.

Intermediate 7:1-{4-[3-(3,⁴-Dichlorophenyl)propyl]morpholin-2-yl}methanamine

A mixture of Intermediate 6 (1.05 g) and2-(oxiran-2-ylmethyl)-1H-isoindole-1,3(2H)-dione (1.10 g) were heated at80° C. under nitrogen for 2 h. The mixture was treated with concentratedsulphuric acid (1.5 ml) then stirred at 150° C. for 18 h. The mixturewas treated with water (100 ml) then washed with ethyl acetate (2×10ml). The dark aqueous phase was basified to ˜pH 11 using 5M aqueoussodium hydroxide then extracted with ethyl acetate (2×100 ml). Thecombined organic extracts were washed with water and brine, dried(Na₂SO₄) and concentrated under vacuum to give the title compound as abrown oil (0.980 g).

LC-MS (System A): Rt 2.05 min.

Intermediate 8: 1-[4-(2,3-Dichlorobenzyl)morpholin-2-yl]methanaminehydrochloride

A mixture of chloromethylpolystyrene-divinylbenzene (Merrifield resin,loaded at 4.0 mmol g⁻¹) (5.0 g) and sodium hydrogen carbonate (14.5 g)in dimethylsulphoxide (80 ml) was heated at 150° C. for 8 h. Thesolution was allowed to cool, left to stand for 24 h, then filtered. Thesolid was washed successively with water (3×100 ml), tetrahydrofuran(3×100 ml) and diethyl ether (3×100 ml), then dried in vacuo to give theformylpolystyrene as a yellow solid which was not characterised. Aportion of this solid (1.0 g) was washed with tetrahydrofuran (5×10 ml)and transferred to a round bottomed flask. 1-Morpholin-2-ylmethanaminedihydrochloride (0.435 g) was dissolved in methanol (10 ml) and loadedequally onto two solid phase extraction columns (Isolute SCX sulphonicacid, 10 g each) which had been prepared by application of methanol.Elution with methanol, then 0.880 ammonia:methanol 10:90 gave a clearcolourless oil (0.280 g). This was added in tetrahydrofuran (2.3 ml) tothe round bottomed flask containing formylpolystyrene and the mixturestirred for 24 h at 20° C. The mixture was then filtered, and the solidwashed with tetrahydrofuran:methanol 1:1 to leave N-{[4-(polystyreneresin)phenyl]methylidene}-1-morpholin-2-ylmethanamine as a yellow solidwhich was not characterised. Two portions of this solid (2×50 mg) in twothick walled glass vials (Reactivials) were each treated withN,N-dimethylformamide (1.25 ml), N,N-diisopropylethylamine (0.097 ml)and 1,2-dichloro-3-(chloromethyl)benzene (0.076 ml), and the mixture wasstirred at 70° C. for 20 h, then allowed to cool. The mixtures werecombined, filtered and washed sequentially with N,N-dimethylformamide(10×10 ml) and tetrahydrofuran (5×10 ml), then treated withtetrahydrofuran:2M aqueous hydrochloric acid solution 3:1 (3 ml). After2 h shaking at 20° C., the mixture was filtered, washed withtetrahydrofuran (4×5 ml) and the filtrate and washings concentrated invacuo to give the title compound as white crystals (0.060 g).

1HNMR (MeOD) 7.85 (1H,dd,aromatic CH), 7.78 (1H,dd,aromatic CH), 7.53(1H,t,aromatic CH), 4.72 (2H,AB,CH₂), 4.30-4.23 (2H,m,2×CH), 4.05(1H,br.t,CH), 3.65 (1H,br.d,CH), 3.58 (1H,br.d,CH), 3.47 (1H,dd,CH),3.30-3.22 (1H,m,2×CH), 3.08 (1H,br.m,CH).

Intermediate 9: 1-[(2S)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methanamine

Intermediate 1 (racemic mixture, 8 g) was separated into its singleenantiomers by preparative chiral-HPLC. The separation was carried outusing a 2″×22 cm Chiralpak AD 20 μm column, Merck self pack DAC system,eluting with 95:5:0.1 (v/v) heptane: absolute ethanol: diethylamine(flow rate: 55 ml/min over 40 min, UV detection 225 nm); sample loadpreparation: 400 mg sample in 20 ml 3:2 (v/v) absolute ethanol: systemeluent.

The title compound (2.49 g) was obtained with preparative HPLC retentiontime 23.0 min.

Intermediate 9A: 1-[(2S)-4-(3,4Dichlorobenzyl)morpholin-2-yl]methanaminesalt with D-tartaric acid 1:1

35% Hydrazine in water (1.8 ml) was added to a slurry of Intermediate 41(5 g) in industrial methylated spirits (75 ml), and the mixture washeated to reflux. Chloroform (75 ml) was added and the mixture washeated under reflux for 65 h. The reaction mixture was cooled to 0-4° C.and allowed to stand for 15 min. The by-product phthalhydrazide wasremoved by vacuum filtration and washed with chloroform (50 ml). Thefiltrate was washed with water (50 ml, 25 ml), dried (MgSO₄), and thesolvent evaporated in vacuo to give an oil. This was dissolved inmethanol (20 ml), which was evaporated in vacuo to give an oil. The oilwas dissolved in methanol (100 ml) and D-tartaric acid (1.05 g) wasadded. The mixture was heated to and maintained at reflux for 30 min.The solution was cooled to 45-50° C., then seeded. The slurry was heldat this temperature for 30 min, then cooled to 0-4° C. and allowed tostand for 30 min. The product was isolated by filtration to give thetitle compound as a white solid (2.59 g).

A sample of the crude D-tartrate salt (500 mg) was dissolved in water(1.4 ml). Methanol (23 ml) was added to give a slurry which was heatedto reflux to give a solution. The mixture was stirred at reflux for 30min, then cooled slowly, seeding at 55° C. The resultant slurry wascooled to 0-4° C. and allowed to stand 30 min. The product was isolatedby filtration to give the title compound as a white solid (0.355 g).

ee: 91.6% ee

LC/MS (System A) R_(t) 1.75 min. Mass spectrum m/z 275/277 [MH⁺]

Chiral analytical HPLC (Chiralpak AD column, 4.6×250 mm, eluent50:50:0.1 MeOH:EtOH:Butylamine, flow rate 0.5 ml/min, UV detection at220 nm), Rt 8.9 min.

Intermediate 9A (Alternative Procedure):1-[(2S)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methanamine salt withD-tartaric acid 1:1

Intermediate 1 (0.613 g) was dissolved in methanol (12.3 ml). D-Tartaricacid (0.335 g) was added and the slurry was heated to reflux for 50 min.The mixture was allowed to cool to 0-5° C. and the precipitate isolatedby filtration to give the title compound as a white solid (0.4 g).

ee: 76%ee

Chiral analytical HPLC (Chiralpak AD column, 4.6×250 mm, eluent50:50:0.1 MeOH:EtOH:Butylamine, flow rate 0.5 ml/min, UV detection at220 nm), Rt 8.9 min.

Intermediate 10: 1-[(2R)-4-(3,4Dichlorobenzyl)morpholin-2-yl]methanamine

Intermediate 10 was prepared in an analogous manner to Intermediate 9yielding the title compound (2.24 g) with preparative HPLC retentiontime 27.8 min.

Intermediate 10A:1-[(2R)-4-(3,4Dichlorobenzyl)morpholin-2-yl]methanamine salt withL-tartaric acid 1:1

[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methylamine (Intermediate 1)(0.500 g) was dissolved in methanol (5 ml). L-Tartaric acid (0.273 g)was added and the mixture was heated to −65° C. to give a milky slurry,and maintained at this temperature for 1 h. Further methanol (5 ml) wasadded and the mixture left to cool slowly to 15-25° C., then cooledfurther to 0-4° C. The mixture was stirred for 30min at this temperatureand the product isolated by filtration to give the title compound as awhite solid (0.38 g).

ee: 78%

LC/MS (System A) Rt 1.75 min. Mass spectrum m/z 275/277 [MH⁺]

Chiral analytical HPLC (Chiralpak AD column, 4.6×250 mm, eluent50:50:0.1 MeOH:EtOH:Butylamine, flow rate 0.5 ml/min, UV detection at220 nm), Rt 10.5 min.

Intermediate 11:Ethyl[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]acetate

A suspension of 4fluorobenzamide (12.9 g) and ethyl4bromo-3-oxopentanoate (Chem Abs No. 3618769-6; 5.24 g) in anhydroustoluene (120 ml) was heated at 140° C. for 19 h, using a Dean-Starktrap. The solution was allowed to cool, filtered, and the residual solidwashed with toluene (30 ml). The combined filtrate and washings wereconcentrated in vacuo to give a brown oil, which was purified by Biotageflash chromatography on silica gel (90 g column), eluting with ethylacetate:cyclohexane (5:95, 7.5:92.5, 10:90), to give the title compoundas a yellow solid (2.98 g).

LC/MS (System A) Rt 3.26 min. Mass spectrum m/z 264 [MH⁺].

Intermediate 12: [2-(4-Fluorophenyl)-5-methyl-1,3-oxazol-4-yl]aceticacid

Intermediate 11 (2.98 g) in ethanol (25 ml) was treated with aqueoussodium hydroxide (2.5M, 18 ml) and the solution stirred at 70° C. for3.5 h then allowed to cool. The material was concentrated in vacuo toremove the ethanol, then the aqueous phase was washed with ethyl acetate(30 ml). The aqueous phase was adjusted to pH 1 by addition of aqueoushydrochloric acid (5M) and the desired acid was extracted into ethylacetate (1×100ml, 1×50 ml). The combined organic phases were washed withdilute aqueous sodium chloride, dried (Na₂SO₄), filtered and thesolution concentrated in vacuo to give the title compound as a creamsolid (2.549).

LC/MS (System A) Rt 2.85 min. Mass Spectrum m/z 236 [MH⁺].

Intermediate 13:1{4-[(5-Chlorothien-2-yl)methyl]morpholin-2-yl}methanamine

Intermediate 13 was prepared in an analogous manner to Intermediate 1(Alternative procedure) from Intermediate 19 and2-chloro-5-(chloromethyl)thiophene, followed by a deprotection reactionyielding the title compound.

Intermediate 14:1-{(2S)-4-[(5-Chlorothien-2-yl)methyl]morpholin-2-yl}methanamine

Intermediate 13 was separated into its single enantiomers by chiralpreparative HPLC to give the title compound in an analogous manner tothe separation of Intermediate 1 to yield Intermediate 9.

LCMS (system A) R_(t) 25.2 min.

Chiral Preparative HPLC retention time 25.2min

Intermediate 14A:1-{(2R)-4-[(5-Chlorothien-2-yl)methyl]morpholin-2-yl}methanamine

Intermediate 14A was prepared in an analogous manner to Intermediate 14yielding the title compound.

LCMS (system A) R_(t) 34 min.

Chiral Preparative HPLC retention time 34 min.

Intermediate 15:N-{[(2S)-4-Benzylmorpholin-2-yl]methyl}-2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)acetamide

A mixture of (5-methyl-2-phenyl-oxazol-4-yl)-acetic acid (0.263 g),1-hydroxylbenzotriazole (0.163 g), and N,N-diisopropylethylamine (0.211ml) in N,N-dimethylformamide (3 ml) was treated with1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.232 g).The mixture was stirred for 5 min, treated with1-[(2S)-4-benzylmorpholin-2-yl]methanamine (prepared in accordance withEP 0 995 746 A1; 0.192 g), and the solution was stirred at 22° C. for 18h. The mixture was partitioned between dichloromethane (20 ml) andsaturated aqueous sodium hydrogen carbonate (10 ml). The phases wereseparated in a hydrophobic frit; the organic phase was loaded onto asolid phase extraction cartridge (10 g SCX) and eluted with methanol,followed by 0.880 ammonia:methanol 10:90 to give the title compound as acolourless gum (0.394 g).

LC/MS (System A) R_(t) 2.42 min. Mass spectrum m/z 406 [MH⁺].

Chiral analytical HPLC, eluent 10% EtOH/n-heptane, R_(t) 18.55 min.

Intermediate 15A: N-{[(2R)Benzylmorpholin-2-yl]methyl}-2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)acetamide

Prepared in an analogous manner to Intermediate 15 from1-[(2R)-4-benzylmorpholin-2-yl]methanamine (prepared in accordance withEP 0 995 746 A1) to obtain the R isomer.

Chiral analytical HPLC eluent 10% EtOH/n-heptane, R_(t) 16.296 min.

Intermediate 16:2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)-N-[(2R)-morpholin-2-ylmethyl]acetamide

A mixture of Intermediate 15 (0.192 g) and ammonium formate (0.4 g) inabsolute ethanol: (2 ml) was treated with 10% palladium on activatedcarbon (0.1 g). After 1.5 h the mixture was treated with ammoniumformate (0.6 g) and stirred under nitrogen for a further 15.5 h. Themixture was filtered through celite and the residue washed with absoluteethanol (20 ml). The solvent was removed at reduced pressure to leave agum. The residue was partitioned between ethyl acetate (20 ml) and 2Nsodium hydroxide (20 ml). The phases were separated and the aqueousphase extracted with ethyl acetate (10 ml). The combined organicextracts were filtered through Whatman silicone treated filter paper andthe solvent removed at reduced pressure to give the title compound(0.077 g) as a colourless gum.

LC/MS (System A) R_(t) 2.14 min. Mass spectrum m/z 316 [MH⁺].

Intermediate 17:2-(5-Methyl-2-phenyl-1,3-oxazol-4-yl)-N-[(2S)-morpholin-2-ylmethyl]acetamide

Intermediate 17 was prepared in an analogous manner to Intermediate 16from Intermediate 15A yielding the title compound

Intermediate 18: {3-[(Methylsulfonyl)amino]phenyl}acetic acid

Methanesulphonylchloride (1.70 ml) was added to a stirred mixture of3-aminophenylacetic acid (3.2 g) and sodium carbonate (5.44 g) in water(36 ml), and the mixture was heated at 85° C. with stirring for 4 h,allowed to cool and acidified with conc. hydrochloric acid to pH 2.After leaving to stand at approximately 4° C. for 18 h, a solid wasfiltered off, and the residue washed with water and ether. The aqueousand ether filtrates were combined and evaporated in vacuo to give asolid, which was dissolved in hot water, the solution was filteredwhilst still hot and the filtrate left to cool before standing at 4° C.for 18 h. The precipitated solid was filtered, washed with a smallquantity of cold water and dried in vacuo to give the title compound asa pale yellow solid (0.417 g).

¹H nmr (400MHz, d₆ DMSO) 12.35 (1H, br, s, COOH), 9.74 ( 1H, s, NH),7.27 (1H, dd, CH), 7.13-7.08 (2H, m, 2×CH), 6.99 (1H, br, d, CH), 3.54(2H, s, CH₂), 2.98 (3H, s CH₃)

LCMS (system A) R_(t) 2.07 min. Mass Spectrum m/z=247 [MNH₄ ⁺] m/z =228[MH⁻].

Intermediate 19: 2,2,2-Trifluoro-N-(morpholin-2-ylmethyl)acetamide

To a stirred solution of morpholin-2-ylmethylamine (3.1 g) in methanol(70 ml) under nitrogen was added an ethereal solution ofethyl-α,α,α-trifluoroacetate (5 ml in 20 ml ether) which had been washedwith saturated aqueous sodium bicarbonate, water and brine, and dried.The mixture was stirred for 30 min at 22° C. before removal of allvolatiles in vacuo. The residue was dissolved in methanol (10 ml) andthe volatiles again removed in vacuo to give the title compound as awhite crunchy foam (4.9 g).

Thermospray Mass Spectrum m/z 213 [MH⁺].

Intermediate 20: 1-[4-(3,4-Difluorobenzyl)morpholin-2-yl]methanamine

Intermediate 20 was prepared in an analogous manner to Intermediate 1(Alternative Procedure) from Intermediate 19 and 3,4-difluorobenzylbromide, followed by deprotection to yield the title compound.

Intermediate 21: 1-[4-(4-Fluorobenzyl)morpholin-2-yl]methanamine

Intermediate 21 was prepared in an analogous manner to Intermediate 1(Alternative Procedure) from Intermediate 19 and 4-fluorobenzylchloride, followed by deprotection to yield the title compound.

Intermediate 22: 1-[(2S)-4-(4-Fluorobenzyl)morpholin-2-yl]methanamine

Intermediate 21 was separated into its single enantiomers by chiralpreparative HPLC to give the title compound in an analogous manner tothe separation of Intermediate 1 to yield Intermediate 9.

LCMS (system A) R_(t) 18.43 min.

Chiral Preparative HPLC Retention time 18.43 min.

Intermediate 23: 1-[(2R)-4-(4-Fluorobenzyl)morpholin-2-yl]methanamine

Intermediate 23 was prepared in an analogous manner to Intermediate 22yielding the title compound.

LCMS (system A) R_(t) 26.56 min.

Chiral Preparative HPLC Retention time 26.56 min.

Intermediate 24: [(2S)-4-(3-chlorobenzyl)morpholin-2-yl]methylamine

Intermediate 24 was prepared in an analogous manner to Intermediate 9

Preparative chiral HPLC retention time 26.1 min

Intermediate 25: [(2S)-4-(2,3-dichlorobenzyl)morpholin-2-yl]methylamine

Intermediate 25 was prepared in an analogous manner to Intermediate 9.

Preparative chiral HPLC retention time 25.3min

Intermediate 26: [(2S)-4-(3,4-difluorobenzyl)morpholin-2-yl]methylamine

Intermediate 26 was prepared in an analogous manner to Intermediate 9.

Preparative chiral HPLC retention time 28.3

Intermediate 27:1-[(cis)-4-(2,5-dichlorobenzyl)-5-methylmorpholin-2-yl]methanamine (2:1Mixture with Trans Isomer)

Intermediate 27 was made in an analogous manner to Intermediate 5.

LC-MS (System A): Rt 1.88 mins Mass Spectrum m/z 289 [MH⁺]

Intermediate 28:2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]-N-[(2R)-morpholin-2-ylmethyl]acetamide

Intermediate 28 was prepared in an analogous manner to Intermediate 16.

LC-MS (System A): Rt 2.21 mins Mass Spectrum m/z 334 [MH⁺]

Intermediate 29: [4-(3-Fluorobenzyl)morpholin-2-yl]methylamine

A mixture of Intermediate 19 (0.300 g) and N,N-diisopropylethylamine(0.372 ml) in N,N-dimethylformamide (5 ml) was treated with3-fluorobenzyl bromide (0.295 g). The solution was stirred at 20° C.under nitrogen for 24 h. The mixture was partitioned betweendichloromethane (10 ml) and saturated aqueous potassium carbonate (10ml). The phases were separated and the organic phase applied to an ionexchange cartridge (10 g Isolute SCX, prewashed with methanol). The SCXcartridge was eluted with methanol (40 ml) followed by 10% 0.880 ammoniain methanol (40 ml) and the appropriate fractions were concentrated invacuo. The residue was dissolved in methanol (2 ml) and treated withaqueous 2N sodium hydroxide (2 ml). The solution was stirred at 20° C.for 24 h. The mixture was partitioned between dichloromethane (15 ml)and water (20 ml). The aqueous extract was washed with dichloromethane(15 ml) and the combined organic extracts concentrated to give the titlecompound as a colourless gum (0.150 g).

Thermospray Mass spectrum m/z 225 [MH⁺].

Intermediate 30:tert-Butyl[(2S)-4-(3,4-dichlorobenzoyl)morpholin-2-yl]methylcarbamate

A mixture of 3,4-dichlorobenzoic acid (0.5 g), 1-hydroxybenzotriazole(0.376 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(0.432 g), and N,N-diisopropylethylamine (0.485 ml) inN,N-dimethylformamide (10 ml) was stirred at 20° C. for 10 min. Themixture was treated with tert-butyl(2R)-morpholin-2-ylmethylcarbamate(0.500 g, known compound WO 9639407A1) and stirred at 20° C. for 24 h.The mixture was partitioned between ethyl acetate (75 ml) and 2N aqueoushydrochloric acid (50 ml). The phases were separated and the organicextract washed with 2N aqueous hydrochloric acid (50 ml), saturatedaqueous sodium hydrogen carbonate (2×50 ml), dried (MgSO₄) and filtered.The solvent was removed in vacuo to give the title compound as a yellowoil, (0.774 g).

LCMS (system A) R_(t) 3.24min Mass Spectrum m/z 389 [MH⁺].

Intermediate 31:1-[(2S)-4-(3,4-dichlorobenzoyl)morpholin-2-yl]methanamine hydrochloride

Intermediate 30 (0.770 g) was treated with 4.0M hydrogen chloride indioxane (8 ml). The mixture was stirred at 20° C. for 30 min. Thesolvent was removed in vacuo to give the title compound as a white solid(0.592 g).

LCMS (system A) R_(t) 2.04min Mass Spectrum m/z 289 [MH⁺]

Intermediate 32: Methyl 4-oxo-3-[(pyridin-3-ylcarbonyl)amino]pentanoate

Nicotinyl chloride hydrochloride (178 mg) was added to a stirredsuspension of aspartic acid β-methyl ester hydrochloride (I83 mg) inpyridine at 0° C. with stirring under nitrogen, and the mixture wasstirred at 0° C. for 1.5 h and at room temperature for 0.5 h. Aceticanhydride (0.37 ml) was added, and the mixture was heated at 90° C. for2 h. Water (0.6 ml) was added and heating continued for 15 min beforethe mixture was partitioned between saturated aqueous sodium bicarbonateand dichloromethane. The organic layer was evaporated in vacuo to give ayellow oil (110 mg).

LC-MS (System A) Rt 1.86 min. Mass Spectrum m/z 251 [MH⁺].

Intermediate 33: Methyl(5-methyl-2-pyridin-3-yl-1,3-oxazol-4-yl)acetate

Intermediate 32 ( 110 mg) was treated with phosphorous oxychloride (0.51ml) in toluene (2 ml) and the mixture heated under reflux for 3.5 h. Themixture was poured into ice cold saturated aqueous sodium bicarbonate(30 ml) and extracted with dichloromethane (20 ml). The organic layerwas evaporated in vacuo to give a yellow gum (111 mg).

LC-MS (System A) Rt 2.30 min. Mass Spectrum m/z 233 [MH⁺].

Intermediate 34: (5-Methyl-2-pyridin-3-yl-1,3-oxazol-4-yl)acetic acid

Intermediate 33 (111 mg) was dissolved in tetrahydrofuran (2 ml) andwater (0.2 ml) and lithium hydroxide (12 mg) added. The mixture wasstirred at 22° C. for 17 h and heated at 60° C. for 2 h. Ethanol (3 ml)and 2N aqueous sodium hydroxide (1 ml) were added, and stirring wascontinued at 22° C. for 2 h. The mixture was applied to a sulphonic acidion exchange cartridge (10 g Isolute SCX) and eluted with methanolfollowed by 10% triethylamine in methanol. Evaporation of thetriethylamine containing fraction gave the title compound as a gum (46mg).

LC-MS (System A) Rt 2.12 min. Mass Spectrum m/z 219 [MH⁺].

Intermediate 35: Ethyl 4-(methylthio)butanoate

A solution of ethyl 4-bromobutyrate (0.269) in N,N-dimethylformamide (3ml) was treated with sodium thiomethoxide (0.103 g), and the mixturestirred at room temperature overnight. The mixture was partitionedbetween water (1ml) and dichloromethane (10 ml), and the organic layerwas washed with 1:1 saturated aqueous sodium chloride and water (10 ml).The organic layers were evaporated in vacuo to give the title compoundas a clear oil (0.135 g).

NMR (CDCl₃) 4.06δ(2H, q, CH₂), 2.46δ(2H, t, CH₂), 2.35δ(2H, t, CH₂),2.03δ(2H, s, CH₃), 1.85δ(2H, m, CH₂), 1.18δ(3H, t, CH₃).

Intermediate 36: Ethyl 4-(methylsulfonyl)butanoate

A solution of Intermediate 35 (0.126 g) in dry dichloromethane (5 ml)was treated with m-chloroperoxybenzoic acid (0.27 g) portion-wise over 5min. The mixture was stirred at room temperature overnight, treated withsaturated aqueous sodium carbonate solution (10 ml) and stirred for ˜5min. The organic layers were separated using a hydrophobic frit andevaporated in vacuo to give the title compound as a pale yellow oil(0.133 g).

NMR (CDCl₃) 4.15δ(2H, q, CH₂), 3.11δ(2H, t, CH₂) 2.93δ(3H, s, CH₃),2.52δ(2H, t, CH₂), 2.17δ(2H, m, CH₂), 1.28δ(3H, t, CH₃).

Intermediate 37: 4-(Methylsulfonyl)butanoic acid

To a solution of Intermediate 36 (0.130 g) in ethanol (2 ml), was added2N aqueous sodium hydroxide (0.75 ml). The mixture was stirred at roomtemperature under nitrogen overnight. The solution was evaporated invacuo to remove the ethanol, and applied to a solid phase extractioncartridge (Isolute SCX sulphonic acid column, 2 g). The cartridge waseluted with methanol (15 ml) and the solvent concentrated in vacuo togive the title compound as a clear oil (0.110 g).

NMR (MeOD) 3.09δ(2H, m, CH₂), 2.88δ(3H, s, CH₃), 2.41δ(2H, t, CH₂),1.98δ(2H, m, CH₂).

Intermediate 38: Methyl[5-(4-fluorophenyl)-1,2,4-oxadiazol-3-yl]acetate

A mixture of 4-fluorobenzamidoxime (1.54 g) and dimethyl malonate (5.7ml) was heated under reflux in para-xylene (20 ml) for 2 h. The mixturewas cooled, washed with 1M aqueous hydrochloric acid, the organic phaseseparated and dried (MgSO₄) and the solvent evaporated in vacuo. Thecolourless oily residue was diluted with toluene and the tolueneevaporated three times; the residue was re-dissolved in dichloromethaneand the solvent evaporated under a stream of nitrogen to give the titlecompound as colourless crystals (1.59 g).

Thermospray Mass Spectrum m/z 237 [MH⁺], 254 [MNH₄ ⁺]

Intermediate 39: Methyl[3-(aminosulfonyl)phenyl]acetate

0.880 Ammonia (0.027 ml) was added to a stirred solution ofmethyl[3-(chlorosulfonyl)phenyl]acetate (0.35 g) in a 1:1 mixture ofdichloromethane and acetonitrile (1.75 ml), and the mixture was stirredat 22° C. for 2 h. The mixture was allowed to stand for a further 18 h,and the solvent was evaporated in vacuo. The residue was re-dissolved indichloromethane and applied to a silica gel cartridge (10 g Varian BondElut, pre-conditioned with dichloromethane). The cartridge was elutedwith dichloromethane, chloroform, ether, ethyl acetate, acetone,acetonitrile and methanol (1 column volume each), the fractionscontaining the product evaporated in vacuo, and the residue passed downa 5 g silica gel cartridge which was prepared and eluted in an identicalmanner. The product containing fractions were evaporated in vacuo togive a residue which was further purified using mass-directedpreparative HPLC, to give the title compound as a colourless gum (0.018g).

LCMS (System A) R_(t) 2.12min Mass Spectrum m/z 230 [MH⁺], 247[MNH₄ ⁺]

Intermediate 40: [3-(Aminosulfonyl)phenyl]acetic acid Compound withN,N,N-triethylamine (1:1)

A portion (0.120 ml) of a solution of sodium hydroxide (0.123 g) inwater (3.05 ml) was added to a stirred solution of Intermediate 39(0.018 g) in methanol (2 ml) and water (1 ml), and stirring wascontinued at 22° C. for 7 h. The pH of the mixture was adjusted toapproximately 8, and the mixture was applied to an aminopropyl ionexchange cartridge (2 g Isolute SPE, pre-conditioned with methanol).Elution with methanol (3 column volumes) followed by of 10%triethylamine in methanol (2 column volumes), and evaporation of thebasic fractions in vacuo gave the title compound as a colourless gum(0.0229).

LCMS (System A) R_(t) 1.75min Mass Spectrum m/z 214 [MH⁻], 233 [MNH₄ ⁺]

Intermediate 41:2-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-1H-isoindole-1,3(2H)-dione

To a solution of 2-(oxiran-2-ylmethyl)-1H-isoindole-1,3(2H)-dione (2 g)in tetrahydrofuran (4 ml) was added 2-[(3,4-dichlorobenzyl)amino]ethanol(2.16 g) with stirring, under a nitrogen atmosphere. The mixture washeated to 66° C. for 22 h, then cooled to 0° C. A further portion oftetrahydrofuran (10 ml) was added, followed by triphenylphosphine (2.88g). Diisopropyl azodicarboxylate (2.2 g) was then added over 10 min. Themixture was stirred at 0° C. for a further 30 min, and at roomtemperature for 14 h. To the crude solution was added ethyl acetate (100ml), then 2M aqueous hydrochloric acid (250 ml). The resulting whiteprecipitate was isolated by filtration, and dried in vacuo to give thetitle compound as its white crystalline hydrochoride salt (2.01 g). Thiswas partitioned between 8% aqueous sodium bicarbonate (200 ml) and ethylacetate (50 ml). The organic phase was separated, dried over magnesiumsulfate and the solvent evaporated in vacuo to give a solid.Dichloromethane (20 ml) was added to the residue and the solvent againevaporated in vacuo to give the title compound as a white solid (1.1 g).

LC/MS R_(t) 2.91 min. Mass Spectrum m/z 405 [MH⁺]

Intermediate 42:N-{[4-(3,4Dichlorobenzyl)morpholin-2-yl]methyl}-2,2,2-trifluoroacetamide

To a stirred solution of Intermediate 19 (3.3 g) inN,N-dimethylformamide (50 ml) under nitrogen was added potassiumcarbonate (2.46 g) and sodium iodide (2.12 g). A solution of3,4-dichlorobenzyl chloride (2 ml) in N,N-dimethylformamide (10 ml) wasadded dropwise to the mixture. The mixture was stirred at 22° C. for 18h before the volatiles were removed in vacuo. The residue waspartitioned between dichloromethane (100 ml) and saturated aqueoussodium carbonate solution (50 ml). The organic phase was subsequentlywashed with additional saturated aqueous sodium carbonate solution (2×50ml) and water (50 ml) before drying over magnesium sulphate, filteringand evaporation of the solvent in vacuo to give a pale yellow oil. Theoil was purified by Biotage flash chromatography on a 90 g silicacartridge eluting with 25% ethyl acetate in cyclohexane, to give thetitle compound as a colourless oil (2.97 g).

LC/MS (System A) R_(t) 2.63 min, Mass Spectrum m/z 371 [MH⁺].

EXAMPLES Example 1N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-phenylacetamide

A mixture of Intermediate 1 (0.028 g) and phenylacetic acid (0.015 g)was treated with 1-methyl-2-pyrrolidinone (0.015 ml) then heated in a600W microwave oven, at full power, for 4 min. The crude mixture waspurified by chromatography on silica gel (Varian Bond-Elut, 1 g) elutingwith cyclohexane/ethyl acetate (4:1 followed by 2:1) to give the titlecompound as a colourless gum (0.029 g).

LC-MS (System A): Rt 2.63 min, Mass Spectrum m/z 393 [MH⁺].

Example 2N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(methylsulfonyl)phenyl]acetamidesalt with formic acid (1:1)

Example 2 was prepared in an analogous manner to Example 1 using amixture of Intermediate 1 (0.055 g) and [4-(methylsulfonyl)phenyl]aceticacid (0.043 g) to give the title compound (0.03 g).

LC-MS (System A): Rt 2.32 mins, Mass Spectrum m/z 471 [MH⁺].

Example 3N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(3-fluorophenyl)acetamide

Example 3 was prepared in an analogous manner to Example 1 using amixture of Intermediate 1 (0.055 g) and (3-fluorophenyl)acetic acid(0.031 g) to give the title compound (0.041 g).

LC-MS (System A): Rt 2.65 mins, Mass Spectrum m/z 411 [MH⁺].

Example 4N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(4-fluorophenyl)acetamide

Example 4 was prepared in an analogous manner to Example 1 using amixture of Intermediate 1 (0.055 g) and (4-fluorophenyl)acetic acid(0.031 g) to give the title compound (0.019 g).

LC-MS (System A): Rt 2.72 mins, Mass Spectrum m/z 411 [MH⁺].

Example 5N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(methylthio)phenyl]acetamide

Example 5 was prepared in an analogous manner to Example 1 using amixture of Intermediate 1 (0.055 g) and 4-(methylthio)phenylacetic acid(0.036 g) to give the title compound (0.028 g).

LC-MS (System A): Rt 2.77 mins, Mass Spectrum m/z 439 [MH⁺].

Example 6N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(3,4-difluorophenyl)acetamide

Example 6 was prepared in an analogous manner to Example 1 using amixture of Intermediate 1 (0.055 g) and (3,4-difluorophenyl)acetic acid(0.034 g) to give the title compound (0.0195 g).

LC-MS (System A): Rt 2.84 mins, Mass Spectrum m/z 429 [MH⁺].

Example 7N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-{4-[(dimethylamino)sulfonyl]phenyl}acetamidesalt with formic acid (1:1)

Example 7 was prepared in an analogous manner to Example 1 using amixture of Intermediate 1 (0.055 g) and{4-[(dimethylamino)sulfonyl]phenyl}acetic acid (0.049 g) to give thetitle compound (0.031 g).

LC-MS (System A): Rt 2.46 mins, Mass Spectrum m/z 500 [MH⁺].

Example 82-(3-Chlorophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

Example 8 was prepared in an analogous manner to Example 1 using amixture of Intermediate 1 (0.055 g) and (3-chlorophenyl)acetic acid(0.0349) to give the title compound (0.034 g).

LC-MS (System A): Rt 2.64 mins, Mass Spectrum m/z 427 [MH⁺].

Example 9N-{[4-(3,4Dichlorobenzyl)morpholin-2-yl]methyl}-2-4-methylphenyl)acetamide

Example 9 was prepared in an analogous manner to Example 1 using amixture of Intermediate 1 (0.055 g) and (4-methylphenyl)acetic acid(0.03 g) to give the title compound (0.0249).

LC-MS (System A): Rt 2.64 mins, Mass Spectrum m/z 407 [MH⁺].

Example 104-[2-({[4-(3,4Dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]benzamide

Example 10 was prepared in an analogous manner to Example 1 using amixture of Intermediate 1 (0.055 g) and [4-(aminocarbonyl)phenyl]aceticacid (0.036 g) to give the title compound (0.01 g).

LC-MS (System A): Rt 2.20 mins, Mass Spectrum m/z 436 [MH⁺].

Example 112-(4-Chlorophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

Example 11 was prepared in an analogous manner to Example 1 using amixture of Intermediate 1 (0.028 g) and (4-chlorophenyl)acetic acid(0.019 g) to give the title compound (0.033 g).

LC-MS (System A): Rt 2.86 min, Mass Spectrum m/z 427 [MH⁺].

Example 12N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(dimethylamino)phenyl]acetamidesalt with formic acid (1:1)

Example 12 was prepared in an analogous manner to Example 1 using amixture of Intermediate 1 (0.055 g) and [4-(dimethylamino)phenyl]aceticacid (0.036 g) to give the title compound (0.025 g).

LC-MS (System A): Rt 2.27 mins, Mass Spectrum m/z 436 [MH⁺].

Example 13N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(2,5-dichlorophenyl)acetamide

Example 13 was prepared in an analogous manner to Example 4 using amixture of Intermediate 1 (0.055 g) and (2,5-dichlorophenyl)acetic acid(0.041 g) to give the title compound (0.025 g).

LC-MS (System A): Rt 2.89 mins, Mass Spectrum m/z 463 [MH⁺].

Example 14N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(trifluoromethyl)phenyl]acetamide

Example 14 was prepared in an analogous manner to Example 1 using amixture of Intermediate 1 (0.055 g) and(4-(trifluoromethyl)phenyl]acetic acid (0.041 g) to give the titlecompound (0.015 g).

LC-MS (System A): Rt 3.00 mins, Mass Spectrum m/z 463 [MH⁺].

Example 15N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(3,4-dichlorophenyl)acetamide

Example 15 was prepared in an analogous manner to Example 1 using amixture of Intermediate 1 (0.055 g) and (3,4-dichlorophenyl)acetic acid(0.041 g) to give the title compound (0.015 g).

LC-MS (System A): Rt 2.93 mins, Mass Spectrum m/z 461 [MH⁺].

Example 162-(2-Chlorophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

Example 16 was prepared in an analogous manner to Example 1 using amixture of Intermediate 1 (0.055 g) and (2-chlorophenyl)acetic acid(0.034 g) to give the title compound (0.025 g).

LC-MS (System A): Rt 2.67 mins, Mass Spectrum m/z 429 [MH⁺].

Example 17:2-[3,5-Bis(trifluoromethyl)phenyl]-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

Example 17 was prepared in an analogous manner to Example 1 using amixture of Intermediate 1 (0.055 g) and[3,5-bis(trifluoromethyl)phenyl]acetic acid (0.054 g) to give the titlecompound (0.04 g).

LC-MS (System A): Rt 3.24 mins, Mass Spectrum m/z 529 [MH⁺].

Example 18N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(2,4-dichlorophenyl)acetamide

Example 18 was prepared in an analogous manner to Example 1 using amixture of Intermediate 1 (0.055 g) and (2,4-dichlorophenyl)acetic acid(0.041 g) to give the title compound (0.019 g).

LC-MS (System A): Rt 2.72 mins, Mass Spectrum m/z 463 [MH⁺].

Example 19N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(4-fluoro-2-methylphenyl)acetamide

Example 19 was prepared in an analogous manner to Example 1 using amixture of Intermediate 1 (0.055 g) and (4-fluoro-2-methylphenyl)aceticacid (0.0349) to give the title compound (0.014 g).

LC-MS (System A): Rt 2.77 mins, Mass Spectrum m/z 425 [MH⁺].

Example 20N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(2,6-dichlorophenyl)acetamide

Example 20 was prepared in an analogous manner to Example 1 using amixture of Intermediate 1 (0.055 g) and (2,6-dichlorophenyl)acetic acid(0.041 g) to give the title compound (0.011 g).

LC-MS (System A): Rt 2.81 mins, Mass Spectrum m/z 463 [MH⁺].

Example 21N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-phenoxyacetamide

Example 21 was prepared in an analogous manner to Example 1 using amixture of Intermediate 1 (0.028 g) and phenoxyacetic acid (0.017 g) togive the title compound (0.026 g).

LC-MS (System A): Rt 2.74 min, Mass Spectrum m/z 409 [MH⁺].

Example 22N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(4-methoxyphenyl)acetamide

Example 22 was prepared in an analogous manner to Example 1 using amixture of Intermediate 1 (0.028 g) and (4-methoxyphenyl)acetic acid(0.018 g) to give the title compound (0.02 g).

LC-MS (System A): Rt 2.66 min, Mass Spectrum m/z 423 [MH⁺].

Example 232-(4-Chlorophenyl)-N-{[4-(3,4-dichlorobenzyl)-5,5-dimethylmorpholin-2-yl]methyl}acetamide

A mixture of Intermediate 3 (0.030 g) and 4-chlorophenylacetic acid(0.020 g) were treated with 1-methyl-2-pyrrolidinone (0.015 ml) thenheated in a 600W microwave oven, at full power, for 4 min. The crudemixture was purified by chromatography on silica gel (Varian Bond-Elutcartridge, 1 g) eluting with cyclohexane/ethyl acetate (19:1 followed by1:1) to give a brown solid which was triturated with ether to give thetitle compound as an off-white solid (0.018 g).

LC-MS (System A): Rt 3.21 min, Mass Spectrum m/z 455 [MH⁺].

Example 24N-{[(cis)-4-(3,4-Dichlorobenzyl)-5-methylmorpholin-2-yl]methyl}-2-phenylacetamide

A mixture of Intermediate 5 (0.060 g) and phenylacetic acid (0.027 g)was treated with 1-methyl-2-pyrrolidinone (0.015 ml) then heated in a600W microwave oven, at full power, for 4 min. The crude mixture waspurified by normal phase preparative HPLC to give the title compound asa colourless gum (27 mg).

LC-MS (System A): Rt 2.85 min, Mass Spectrum m/z 407 [MH⁺].

Example 25N-{[(trans)-4-(3,4-Dichlorobenzyl)-5-methylmorpholin-2-yl]methyl}-2-phenylacetamide

Example 25 was prepared in an analogous manner to Example 24 using amixture of Intermediate 5 (0.06 g) and phenylacetic acid (0.027 g) togive the title compound as a colourless gum (18 mg).

LC-MS (System A): Rt 2.85 min, Mass Spectrum m/z 407 [MH⁺].

Example 262-(4-Chlorophenyl)-N-{[(cis)-4-(3,4-dichlorobenzyl)-5-methylmorpholin-2-yl]methyl}acetamide

Example 26 was prepared in an analogous manner to Example 24 using amixture of Intermediate 5 (0.06 g) and (4-chlorophenyl)acetic acid(0.034 g) to give the title compound (0.027 g).

LC-MS (System A): Rt 3.10 min, Mass Spectrum m/z 441 [MH⁺].

Example 272-(4-Chlorophenyl)-N-{[(trans)-4-(3,4-dichlorobenzyl)-5-methylmorpholin-2-yl]methyl}acetamide

Example 27 was prepared in an analogous manner to Example 24 using amixture of Intermediate 5 (0.06 g) and (4-chlorophenyl)acetic acid(0.034 g) to give the title compound (0.018 g).

LC-MS (System A): Rt 3.10 min, Mass Spectrum m/z 441 [MH⁺].

Example 28N-({4-[3-(3,4-Dichlorophenyl)propyl]morpholin-2-yl}methyl)-2-phenylacetamide

A mixture of Intermediate 7 (0.030 g) and phenylacetic acid (0.015 g)was treated with 1-methyl-2-pyrrolidinone (0.015 ml) then heated in a600W microwave oven, at full power, for 4 min. The crude mixture waspurified by chromatography on silica gel (Varian Bond-Elut, 1 g) elutingwith cyclohexane/ethyl acetate (4:1 followed by 2:1) to give the titlecompound as a colourless gum (0.0049).

LC-MS (System A): Rt 2.74 min, Mass Spectrum m/z 421 [MH⁺].

Example 292-(4Chlorophenyl)-N-{[4-(2,3-dichlorobenzyl)morpholin-2-yl]methyl}acetamidetrifluoroacetate

Intermediate 8 (0.060 g) was dissolved in methanol (10 ml) and loadedonto a solid phase extraction column (2 g Isolute SCX sulphonic acid)which had been prepared by application of methanol. Elution withmethanol, then 0.880 ammonia:methanol 10:90 gave a clear colourless gum(0.027 g). This was treated with (4chlorophenyl)acetic acid (0.017 g)and N-methyl-2-pyrrolidinone (1 drop) and subjected to microwaveirradiation (600W, full power, 4 min). Purification by automatedpreparative HPLC (gradient profile 30-60% (ii) over 20 mins, R_(t) 13mins) gave the title compound (0.0189) as a white solid.

LC/MS (System A): R_(t) 2.87 min, Mass spectrum m/z 429 [MH⁺].

Example 301-(4-Chlorophenyl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}cyclopropanecarboxamidetrifluoroacetate

Example 30 was prepared in an analogous manner to Example 1 using amixture of Intermediate 1 (0.055 g) and1-(4-chlorophenyl)cyclopropanecarboxylic acid (0.039 g) to give thetitle compound (0.008 g).

LC-MS (System A): Rt 3.03 mins, Mass Spectrum m/z 455 [MH⁺].

Example 31N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(5-methoxy-2-methyl-1H-indol-3-yl)acetamide

Example 31 was prepared in an analogous manner to Example 1 using amixture of Intermediate 1 (0.056 g) and(5-methoxy-2-methyl-1H-indol-3-yl)acetic acid (0.044 g) to give thetitle compound (0.019 g).

LC-MS (System A): Rt 2.63 mins, Mass Spectrum m/z 476 [MH⁺].

Example 32N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-thien-3-ylacetamide

Example 32 was prepared in an analogous manner to Example 1 using amixture of Intermediate 1 (0.056 g) and thien-3-ylacetic acid (0.028 g)to give the title compound (0.016 g).

LC-MS (System A): Rt 2.50 mins, Mass Spectrum m/z 399 [MH⁺].

Example 33N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)acetamide

Example 33 was prepared in an analogous manner to Example 1 using amixture of Intermediate 1 (0.056 g) and(5-methyl-2-phenyl-1,3-oxazol-4-yl)acetic acid (0.043 g) to give thetitle compound (0.036 g).

LC-MS (System A): Rt 2.80 mins, Mass Spectrum m/z 474 [MH⁺].

Example 34N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(5-methyl-1-phenyl-1H-pyrazol-4-yl)acetamide

Example 34 was prepared in an analogous manner to Example 1 using amixture of Intermediate 1 (0.056 g) and(5-methyl-1-phenyl-1H-pyrazol-4-yl)acetic acid (0.043 g) to give thetitle compound (0.014 g).

LC-MS (System A): Rt 2.61 mins, Mass Spectrum m/z 473 [MH⁺].

Example 352-(4Bromo-3,5-dimethyl-1H-pyrazol-1-yl)-N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide

Example 35 was prepared in an analogous manner to Example 1 using amixture of Intermediate 1 (0.056 g) and(4-bromo-3,5dimethyl-1H-pyrazol-1-yl)acetic acid (0.047 g) to give thetitle compound (0.032 g).

LC-MS (System A): Rt 2.70 mins, Mass Spectrum m/z 491 [MH⁺].

Example 36N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(2-phenyl-1,3-thiazol-4-yl)acetamide

Example 36 was prepared in an analogous manner to Example 1 using amixture of Intermediate 1 (0.056 g) and(2-phenyl-1,3-thiazol-4-yl)acetic acid (0.042 g) to give the titlecompound (0.0499).

LC-MS (System A): Rt 2.85 mins, Mass Spectrum m/z 476 [MH⁺].

Example 37N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(2-pyrazin-2-yl-1,3-thiazol-4-yl)acetamide

Example 37 was prepared in an analogous manner to Example 1 using amixture of Intermediate 1 (0.056 g) and(2-pyrazin-2-yl-1,3-thiazol-4-yl)acetic acid (0.044 g) to give the titlecompound (0.05 g).

LC-MS (System A): Rt 2.43 mins, Mass Spectrum m/z 478 [MH⁺].

Chiral analytical HPLC, eluent 60% EtOH/n-heptane: Rt 9.22 min and 12.42min.

Example 38N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(2-furyl)acetamide

Example 38 was prepared in an analogous manner to Example 1 using amixture of Intermediate 1 (0.056 g) and 2-furylacetic acid (0.025 g) togive the title compound (0.044 g).

LC-MS (System A): Rt 2.38 mins, Mass Spectrum m/z 383 [MH⁺].

Example 39N-{[(2S)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(methylsulfonyl)phenyl]acetamide(Single Enantiomer of Example 2)

Example 39 was prepared in an analogous manner to Example 1 using amixture of Intermediate 9 (0.055 g) and 4-(methylsulphonyl)phenylaceticacid (0.050 g) to give the title compound (0.045 g).

Chiral analytical HPLC, eluent 35% EtOH/n-heptane, Rt 20.56 min

Example 40N-{[(2R)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-[4-(methylsulfonyl)phenyl]acetamide

Example 40 was prepared in an analogous manner to Example 1 using amixture of Intermediate 10 (0.055 g) and 4-(methylsulphonyl)phenylaceticacid (0.050 g) to give the title compound (0.046 g).

Chiral analytical HPLC, eluent 35% EtOH/n-heptane, Rt 17.16 min

Example 41N-{[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazolyl]acetamide

Intermediate 12 (0.050 g) was treated with N,N-dimethylformamide (0.5ml) followed by 1-hydroxybenzotriazole hydrate (0.027 g),1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.0449)and Intermediate 1 (0.042 g) in N,N-dimethylformamide (0.5 ml) andN,N-diisopropylethylamine (0.027 ml). The mixture was stirred at 22° C.for 20 h, then left to stand for 6 days. The solution was diluted withdichloromethane (10 ml) and washed successively with dilute aqueoussodium hydrogen carbonate (10 ml) and dilute aqueous sodium chloride(2×10 ml). The organic phase was isolated using a hydrophobic frit (6ml) and drained directly onto an SCX column (2 g Isolute SPE) which hadbeen prepared by application of methanol. Elution with methanol, then0.880 ammonia:methanol 10:90 gave the title compound (0.048 g) as anorange glassy solid.

LC/MS (System A) Rt 2.93 min. Mass spectrum m/z 492 [MH⁺].

Example 42N-{[(2S)-4-(3,4Dichlorobenzyl)morpholin-2-yl]methyl}-2-(2-pyrazin-2-yl-1,3-thiazol-4-yl)acetamide

Chiral separation from the racemic mixture of Example 37:

Example 37 was separated into its single enantiomers with a chiralpreparative HPLC system. The separation was carried out using aChiralpak AD column (2 cm×25 cm), eluting with 60% ethanol in heptane(15 ml/min over 25 mins, UV detection λ=215 nm) to give the S isomer.

Chiral analytical HPLC, eluent 60% EtOH/n-heptane: Rt 12.22 min.

Example 43N-{[(2R)-4-(3,4Dichlorobenzyl)morpholin-2-yl]methyl}-2-(2-pyrazin-2-yl-1,3-thiazol-4-yl)acetamide

Example 43 was prepared in an analogous manner to Example 42 whichsimilarly obtained the R isomer.

Chiral analytical HPLC, eluent 60% EtOH/n-heptane: Rt 9.20 min.

Example 44N-[{(2S)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(5-phenyl-2H-tetraazol-2-yl)acetamide

A solution of (5-phenyl-2H-tetraazol-2-yl)acetic acid (0.082 g) inN,N-dimethylformamide (2 ml) under nitrogen was treated withO-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethylammoniumhexafluorophosphate (0.152 g) and N,N-diisopropylethylamine (0.139 ml)followed by a solution of Intermediate 9 (0.110 g) inN,N-dimethylformamide (3 ml), and the mixture was stirred at 22° C. for4 h. The solvent was removed in vacuo and the residue dissolved in ethylacetate (20 ml). The solution was washed with 10% aqueous citric acid(20 ml), brine (20 ml), saturated aqueous sodium hydrogen carbonate (20ml) and brine (20 ml), dried (MgSO₄) and evaporated in vacuo.Purification by flash chromatography on silica gel (Merck 9385), elutingwith ethyl acetate, followed by trituration of the resultant productwith diethyl ether, gave the title compound as a white solid (0.184 g).

LCMS (System A): Rt 2.85 min. Mass Spectrum m/z 461 [MH⁺].

Example 45N-{[4-(3,4-Difluorobenzyl)morpholin-2-yl]methyl}-2-4-[(methylsulfonyl)amino]phenyl}acetamide

Example 45 was prepared in an analogous manner to Example 44 using amixture of Intermediate 24 (0.014 g) and{4-[(methylsulfonyl)amino]phenyl}acetic acid (0.013 g) to give the titlecompound (0.022 g).

LC-MS (System A) Rt 2.09 mins. Mass Spectrum m/z 454 [MH⁺].

Example 46N-{[(2S)-4-(4-Fluorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)amino]phenyl}acetamide

Example 46 was prepared in an analogous manner to Example 44 using amixture of Intermediate 24 (0.09 g) and4-(methylsulphonylamino)phenylacetic acid (0.1 g) to give the titlecompound (0.077 g).

LC-MS (System A) Rt 2.05 mins. Mass Spectrum m/z 436 [MH⁺].

Chiral analytical HPLC, eluent 15% EtOH/n-heptane: Rt 23.09 min.

Example 47N-{[(2R)-4-(4-Fluorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)amino]phenyl}acetamide

Example 47 was prepared in an analogous manner to Example 44 using amixture of Intermediate 24 (0.023 g) and4-(methylsulphonylamino)phenylacetic acid (0.025 g) to give the titlecompound (0.01 g).

LC-MS (System A) Rt 2.06 mins. Mass Spectrum m/z 436 [MH⁺].

Chiral analytical HPLC, eluent 15% EtOH/n-heptane: Rt 18.78 min.

Example 48N-{[4-(4-Fluorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)amino{phenyl}acetamide

Example 48 was prepared in an analogous manner to Example 44 using amixture of Intermediate 24 (0.013 g) and4-(methylsulphonylamino)phenylacetic acid (0.013 g), with the exceptionthat 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride and1-hydroxybenzotriazole were used as the coupling reagents to give thetitle compound (0.019 g).

LC-MS (System A) Rt 2.01 mins Mass Spectrum m/z 436 [MH⁺].

Chiral analytical HPLC, eluent 15% EtOH/n-heptane: Rt 19.40 min and23.51 min.

Example 49N-({(2S)-4-[(5-Chlorothien-2-yl)methyl]morpholin-2-yl}methyl)-2-{3-[(methylsulfonyl)amino]phenyl}acetamide

Example 49 was prepared in an analogous manner to Example 44 using amixture of Intermediate 14 (0.1 g) and Intermediate 18(0.1 g) to givethe title compound (0.102 g).

LC-MS (System A) Rt 2.23 mins. Mass Spectrum m/z 458 [MH⁺].

Chiral analytical HPLC, eluent 20% EtOH/n-heptane: Rt 13.18 min.

Example 50N-({(2R)-4-[(5-Chlorothien-2-yl)methyl]morpholin-2-yl}methyl)-2-{3-[(methylsulfonyl)amino]phenyl}acetamide

Example 50 was prepared in an analogous manner to Example 44 using amixture of Intermediate 14A (0.1 g) and Intermediate 18 (0.1 g) to givethe title compound (0.085 g).

LC-MS (System A) Rt 2.27 mins. Mass Spectrum m/z 458 [MH⁺].

Chiral analytical HPLC, eluent 20% EtOH/n-heptane: Rt 10.65 min.

Example 51N-({4-[(5-Chlorothien-2-yl)methyl]morpholin-2-yl}methyl}-2-3-[(methylsulfonyl)amino]phenyl}acetamide

Example 51 was prepared in an analogous manner to Example 44 using amixture of Intermediate 24 (0.007 g) and Intermediate 18 (0.007 g) withthe exception that 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimidehydrochloride and 1-hydroxybenzotriazole were used as the couplingreagents to give the title compound (0.0077 g).

LC-MS (System A) Rt 2.29 mins. Mass Spectrum m/z 458 [MH⁺].

Chiral analytical HPLC, eluent 20% EtOH/n-heptane: Rt 10.67 min and13.23 min.

Example 52N-{[4-(3,4Dichlorobenzyl)morpholin-2-yl]methyl}-2-(2,6-difluorophenyl)acetamide

Example 52 was prepared in an analogous manner to Example 1 using amixture of Intermediate 1 (0.055 g) and 2,6-difluorophenylacetic acid(0.035 g) to give the title compound (0.057 g).

LC-MS (System A) Rt 2.70 mins. Mass Spectrum m/z 429 [MH⁺].

Example 53N-Cyclopropyl-3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]benzamide

A mixture of Example 57 (0.300 g), 1-hydroxybenzotriazole (0.171 g) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.098 g)was stirred in N,N-dimethylformamide (6.6 ml) andN,N-diisopropylethylamine (0.190 ml) was added. The mixture was stirredat 20° C. until a clear solution was obtained. A portion of the mixture(1.1 ml) was transferred into a flask, cyclopropylamine (0.00-77 ml) wasadded, and the mixture was stirred at 20° C. under nitrogen for 17 h.Polystyrene methylisocyanate (Argonaut Technologies, 0.034g, loading1.57 mmol/g) and macroporous triethylammonium methylpolystyrenecarbonate (Argonaut Technologies, 0.0159, loading 3.2 mmol/g) wereadded, and stirring was continued for 1 h. The mixture was filtered, theresin beads washed with methanol and the combined filtrates reduced involume to approximately 1 ml and purified by solid phase extraction (2 gSCX cartridge), eluting with methanol followed by 10% 0.880 ammonia inmethanol. The product was isolated by evaporation of the solvent fromthe basic fraction and was further purified by solid phase extraction (5g Varian Bondelut silica gel cartridge), eluting successively with onecolumn volume of dichloromethane, chloroform, ether, ethylacetate,acetone, acetonitrile and methanol, to give the title compound as acolourless gum (0.034 g).

LCMS (system A) R_(t) 2.65 min. Mass Spectrum m/z 476, 478 [MH⁺].

Example 54N-{[(2S)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)acetamide

Intermediate 16 (0.077 g) in anhydrous N,N-dimethylformamide (2 ml) wastreated with N,N-diisopropylethylamine (0.044 ml) and 3,4-dichlorobenzylchloride (0.035 ml). The mixture was stirred at 22(C for 19 h, andpartitioned between chloroform (15 ml) and saturated aqueous sodiumbicarbonate (15 ml). The phases were separated using a hydrophobic fritand the organic phase loaded onto a solid phase extraction column (10 gSCX). Elution with methanol, then 0.880 ammonia:methanol 10:90 gave aclear colourless gum. The crude mixture was purified by flashchromatography on silica gel (Trikonex Flashtube™ 2008, 8 g), elutingwith ethyl acetate, to give the title compound as a colourless gum(0.0023 g).

LC/MS (System A) Rt 2.88 min. Mass spectrum m/z 474 [MH⁺].

Chiral analytical HPLC, eluent 10% EtOH/n-heptane, Rt 12.39 min.

Example 54 (Alternative Procedure)N-{[(2S)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)acetamide

Example 54 was prepared in an analogous manner to Example 1 using amixture of Intermediate 9 (0.055 g) and2-phenyl-5-methyl-4-oxazolylacetic acid (0.050 g) to give the titlecompound (0.046 g).

LC-MS (System A) Rt 2.88 mins. Mass Spectrum m/z 474 [MH⁺].

Example 55N-{[(2R)-4-(3,4Dichlorobenzyl)morpholin-2-yl]methyl}-2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)acetamide

Example 55 was prepared in an analogous manner to that described inExample 54 using Intermediate 17 (0.081 g) and 3,4-dichlorobenzylchloride (0.037 ml) to give a colourless gum (0.011 g).

LC/MS (System A) R_(t) 2.87 min. Mass spectrum m/z 474 [MH⁺].

Chiral analytical HPLC, eluent 10% EtOH/n-heptane, R_(t) 9.812 min.

Example 55 (Alternative Procedure)N-{[(2R)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(5-methyl-2-phenyl-1,3-oxazolyl)acetamide

Example 55 was prepared in an analogous manner to Example 1 using amixture of Intermediate 10 (0.055 g) and2-phenyl-5-methyl-4-oxazolylacetic acid (0.050 g) to give the titlecompound (0.042 g).

LC-MS (System A) Rt 2.88 mins. Mass Spectrum m/z 474 [MH⁺].

A mixture of Examples 54 and 55: Chiral analytical HPLC, eluent 10%EtOH/n-heptane, R_(t) 9.73 and 12.42 min.

Example 56 Methyl3-[2-({[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]benzoate

A mixture of [3-(methoxycarbonyl)phenyl]acetic acid (0.200 g),Intermediate 1 (0.2849), 1-hydroxybenzotriazole (0.182 g) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.316 g)was stirred in dichloromethane (10 ml), and N,N-diisopropylethylamine(0.352 ml) was added to the solution. Stirring at 20° C. under nitrogenwas continued for 8 h. The mixture was purified by solid phaseextraction (2×10 g Varian Bondelut silica gel cartridges), elutingsuccessively with one column volume of dichloromethane, chloroform,ether, ethyl acetate, acetone, acetonitrile and methanol, to give thetitle compound as a colourless gum, (0.266 g).

LCMS (system A) R_(t) 2.70 min. Mass Spectrum m/z=451, 453 [MH⁺].

Example 573-[2-({[4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}amino)-2-oxoethyl]benzoicacid Compound with N,N,N-triethylamine (1:1)

To a solution of Example 56 (0.261 g) in a mixture of water (4 ml) andmethanol (12 ml) was added a solution of sodium hydroxide (0.054 g) inwater (0.5 ml) and the mixture was stirred at 20° C. for 72 h. The pH ofthe mixture was adjusted to approximately 6 by the addition of 2Nhydrochloric acid and the mixture was purified by solid phase extraction(10 g SCX cartridge), eluting with methanol followed by 10%triethylamine in methanol. Evaporation of the basic fraction in vacuogave the title compound as a colourless gum, (0.319 g).

LCMS (system A) R_(t) 2.66 min. Mass Spectrum m/z 437, 439 [MH⁺].

Examples 58-85

Preparation Name analogous to Characterising Data 582-[3-(acetylamino)phenyl]-N-{[4- Example 1 LC-MS(System A):(3,4-dichlorobenzyl)morpholin-2- Rt 2.33 mins. yl]methyl}acetamide MassSpectrum m/z 450[MH⁺]. 59 2-(3-acetyl-1-benzothien-4-yl)-N- Example 1LC-MS(System A): {[4-(3,4-dichlorobenzyl)morpholin-2- Rt 2.90 mins.yl]methyl}acetamide trifluoroacetate Mass Spectrum m/z 491[MH⁺]. 602-(5-bromopyridin-3-yl)-N-{[4-(3,4- Example 1 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt 2.57 mins. yl]methyl}acetamide compoundwith Mass Spectrum m/z 474[MH⁺]. formic acid (1:1) 61 N-{[4-(3,4-Example 1 LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.51 mins.yl]methyl}-2-(2,3- Mass Spectrum m/z 473[MH⁺].dimethylquinoxalin-6-yl)acetamide 62 2-(4-acetylphenyl)-N-{[4-(3,4-Example 1 LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.57 mins.yl]methyl}acetamide trifluoroacetate Mass Spectrum m/z 435[MH⁺]. 632-(4-acetylphenyl)-N-{[4-(3,4- Example 41 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt 2.57 mins. yl]methyl}acetamide MassSpectrum m/z 435[MH⁺]. 64 N-{[4-(3,4- Example 1 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt 2.84 mins. yl]methyl}-2-(4- Mass Spectrumm/z 463[MH⁺]. isobutyrylphenyl)acetamide trifluoroacetate 65 methyl4-[2-({[4-(3,4- Example 1 LC-MS(System A): dichlorobenzyl)morpholin-2-Rt 2.65 mins. yl]methyl}amino)-2- Mass Spectrum m/z 451[MH⁺].oxoethyl]benzoate trifluoroacetate 66 methyl 4-[2-({[4-(3,4- Example 56LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.73 mins.yl]methyl}amino)-2- Mass Spectrum m/z 451[MH⁺]. oxoethyl]benzoate 672-(4-cyanophenyl)-N-{[4-(3,4- Example 1 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt 2.60 mins. yl]methyl}acetamidetrifluoroacetate Mass Spectrum m/z 418[MH⁺]. 682-(4-cyanophenyl)-N-{[4-(3,4- Example 41 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt 2.63 mins. yl]methyl}acetamide MassSpectrum m/z 418[MH⁺]. 69 N-{[(2S,5R)-4-(3,4-dichlorobenzyl)- Example 24LC-MS(System A): 5-methylmorpholin-2-yl]methyl}-2- from (2R)-2- Rt 2.88mins. phenylacetamide aminopropan- Mass Spectrum m/z 407[MH⁺]. 1-ol 702-(4-chlorophenyl)-N-{[(2S,5R)-4- Example 24 LC-MS(System A):(3,4-dichlorobenzyl)-5- Rt 3.13 mins. methylmorpholin-2- Mass Spectrumm/z 441[MH⁺]. yl]methyl}acetamide 71 N-{[4-(3,4- Example 1 LC-MS(SystemA): dichlorobenzyl)morpholin-2- Rt 2.66 mins. yl]methyl}-2-(3-fluoro-4-Mass Spectrum m/z 427[MH⁺]. hydroxyphenyl)acetamide trifluoroacetate 72N-{[(2S)-4-(3,4- Example 42 LC-MS(System A): dichlorobenzyl)morpholin-2-Rt 2.38 mins. yl]methyl}-2-(2-furyl)acetamide Mass Spectrum m/z383[MH⁺]. Chiral Analytical HPLC Eluent 20% EtOH/heptane Rt 9.97 mins.73 N-{[4-(3,4- Example 53 LC-MS(System A): dichlorobenzyl)morpholin-2-Rt 2.25 mins. yl]methyl}-2-{4-[(4-methylpiperazin- Mass Spectrum m/z519[MH⁺]. 1-yl)carbonyl]phenyl}acetamide 74 4-[2-({[4-(3,4- Example 53LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.13 mins.yl]methyl}amino)-2-oxoethyl]-N-[2- Mass Spectrum m/z 507[MH⁺].(dimethylamino)ethyl]benzamide 75 4-[2-({[4-(3,4- Example 53LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.53 mins.yl]methyl}amino)-2-oxoethyl]-N,N- Mass Spectrum m/z 464[MH⁺].dimethylbenzamide 76 4-[2-({[4-(3,4- Example 53 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt 2.57 mins.yl]methyl}amino)-2-oxoethyl]-N- Mass Spectrum m/z 464[MH⁺].ethylbenzamide 77 4-[2-({[4-(3,4- Example 53 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt 2.28 mins.yl]methyl}amino)-2-oxoethyl]-N-(2- Mass Spectrum m/z 480[MH⁺].hydroxyethyl)benzamide 78 N-{[4-(3,4- Example 53 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt 2.45 mins. yl]methyl}-2-[4-(morpholin-4-Mass Spectrum m/z 506[MH⁺]. ylcarbonyl)phenyl]acetamide 79N-{[(2S)-4-(3,4- Example LC-MS(System A): dichlorobenzyl)morpholin-2-162 Rt 2.66 mins. yl]methyl}-2-{3- Mass Spectrum m/z 500[MH⁺].[(dimethylamino)sulfonyl]phenyl} acetamide 80 N-{[(2R)-4-(3,4- Example42 LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.81 mins.yl]methyl}-2-{4- Mass Spectrum m/z 500[MH⁺].[(dimethylamino)sulfonyl]phenyl} Chiral Analytical HPLC acetamide Eluent40% EtOH/heptane Rt 13.10 min. 81 N-{[(2S)-4-(3,4- Example LC-MS(SystemA): dichlorobenzyl)morpholin-2- 162 Rt mins 2.62. yl]methyl}-2-{4- MassSpectrum m/z 500[MH⁺]. [(dimethylamino)sulfonyl]phenyl} acetamide 824-[2-({[4-(3,4- Example 53 LC-MS(System A): dichlorobenzyl)morpholin-2-Rt 2.49 mins. yl]methyl}amino)-2-oxoethyl]-N- Mass Spectrum m/z450[MH⁺]. methylbenzamide 83 4-[2-({[4-(3,4- Example 53 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt 2.69 mins.yl]methyl}amino)-2-oxoethyl]-N- Mass Spectrum m/z 478[MH⁺].isopropylbenzamide 84 N-cyclopropyl-4-[2-({[4-(3,4- Example 53LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.61 mins.yl]methyl}amino)-2- Mass Spectrum m/z 476[MH⁺]. oxoethyl]benzamide 854-[2-({[4-(3,4- Example 53 LC-MS(System A): dichlorobenzyl)morpholin-2-Rt 2.57 mins. yl]methyl}amino)-2-oxoethyl]-N-(2- Mass Spectrum m/z494[MH⁺]. methoxyethyl)benzamide

Example 86N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-(5-phenyl-2H-tetraazol-2-yl)acetamide

2-(3,5-Dimethoxy-4-formylphenoxy)ethoxymethyl polystyrene resin(Novabiochem, loading 0.9 mmol/g, 1 g) was swollen with the minimumquantity of 1% acetic acid/N,N-dimethylformamide to form a slurry.Intermediate 1 (0.969 g) was added to this mixture inN,N-dimethylformamide (2 ml) and the mixture shaken at room temperaturefor 100 min. 1% Acetic acid/N,N-dimethylformamide (10 ml) was addedfollowed by sodium triacetoxyborohydride (333 mg). The mixture was thenshaken for 20 min before further sodium triacetoxyborohydride (0.300 g)was added, and shaking was continued at room temperature for 18 h. Thereaction solution was then drained off and the resin washed with(N,N-dimethylformamide: 5×10 ml, methanol: 5×10 ml, dichloromethane:5×10 ml, diethyl ether: 3×10 ml). The resin was then dried in vacuo.

The resin (0.100 g) was then swollen with dichloromethane, and excesssolvent drained off. A solution of diisopropylcarbodiimide (0.0705 ml)and bromo acetic acid (0.125 g) in 1:1 dichloromethane/dimethylformamide (1 ml), was made and stirred for ca. 5 min, before adding tothe resin. The resin was then shaken at room temperature for 2 h. Thesolution was drained off and the resin washed with(N,N-dimethylformamide: 5×10 ml, methanol: 5×10 ml, dichloromethane:5×10 ml).

A solution of potassium tert-butoxide (0.050 g) and the azole5-phenyl-1-H-tetrazole (0.131 g) in N,N-dimethylformamide (1 ml) wasprepared and stirred for 5 min before this was added to the resin. Thereaction mixture was heated to 60° C. and shaken for 18 h. The reactionsolution was then drained off and the resin washed with(N,N-dimethylformamide: 5×1 ml, methanol: 5×1 ml, dichloromethane: 5×1ml).

1:1 trifluoroacetic acid/dichloromethane solution (1 ml) was then addedto the resin, and the mixture shaken for 90 min. The resin was filteredoff, washed with dichloromethane (1 ml), and the combined filtrate andwashings evaporated. The resulting solid was purified by mass directedpreparative HPLC to give the title compound (15 mg).

LC-MS (System A) R_(t) 2.77 min. Mass Spectrum m/z 461 [MH⁺].

Examples 87-90

Preparation Name analogous to Characterising Data 872-(4-bromo-1H-imidazol-1-yl)-N-{[4- Example 86 LC-MS(System A):(3,4-dichlorobenzyl)morpholin-2- Rt 2.34 mins. yl]methyl}acetamide MassSpectrum m/z 462[MH⁺]. 88 N-{[4-(3,4- Example 56 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt 2.92 mins. yl]methyl}-2-(4- Mass Spectrumm/z 438[MH⁺]. nitrophenyl)acetamide 89 N-{[4-(3,4- Example 56LC-MS(System A): dichlorobenzyl)morpholin-2- Rt mins 2.92.yl]methyl}-2-(3- Mass Spectrum m/z 438[MH⁺]. nitrophenyl)acetamide 902-[3-(acetylamino)phenyl]-N-{[4-(3- Example 91 LC-MS(System A):fluorobenzyl)morpholin-2- Rt 2.13 mins. yl]methyl}acetamide MassSpectrum m/z 400[MH⁺].

Example 91N-{[4-(3-fluorobenzyl)morpholin-2-yl]methyl}-2-{4-[(methylsulfonyl)amino]phenyl}acetamide

A mixture of Intermediate 29 (0.0134 g),{4-[(methylsulfonyl)amino]phenyl}acetic acid (0.0137 g, known compoundWO 9929655 A1), 1-hydroxybenzotriazole (0.0097 g) andN,N-diisopropylethylamine (0.01 ml) in N,N-dimethylformamide (0.5 ml)was treated with a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.00138 g)in N,N-dimethylformamide (0.5 ml). The mixture was stirred at 20° C. for24 h. The mixture was partitioned between dichloromethane (4 ml) andsaturated aqueous sodium hydrogen carbonate (4 ml). The phases wereseparated and the organic phase applied to an ion exchange cartridge (2g Isolute SCX, prewashed with methanol). The SCX cartridge was elutedwith methanol (10 ml) followed by 10% 0.880 ammonia in methanol (10 ml)and the appropriate fractions were concentrated in vacuo to give thetitle compound as a colourless gum (0.0174 g).

LCMS (system A) R_(t) 2.14 min. Mass Spectrum m/z 436 [MH⁺].

Examples 92-134

Preparation Name analogous to Characterising Data 922-[3-(acetylamino)phenyl]-N-{[4- Example 91 LC-MS(System A):(3,4-difluorobenzyl)morpholin-2- Rt 2.31 mins. yl]methyl}acetamide MassSpectrum m/z 418[MH⁺]. 93 2-[4-(acetylamino)phenyl]-N-{[4- Example 91LC-MS(System A): (3,4-difluorobenzyl)morpholin-2- Rt 2.10 mins.yl]methyl}acetamide Mass Spectrum m/z 418[MH⁺]. 94 N-{[4-(3,4- Example91 LC-MS(System A): difluorobenzyl)morpholin-2- Rt 2.09 mins.yl]methyl}-2-(2-pyrazin-2-yl-1,3- Mass Spectrum m/z 554[MH⁺].thiazol-4-yl)acetamide 95 N-{[4-(3,4- Example 91 LC-MS(System A):difluorobenzyl)morpholin-2- Rt 2.13 mins. yl]methyl}-2-{3- Mass Spectrumm/z 446[MH⁺]. [(methylsulfonyl)amino]phenyl} acetamide 96 N-{[4-(3,4-Example 91 LC-MS(System A): difluorobenzyl)morpholin-2- Rt 2.04 mins.yl]methyl}-2-[3- Mass Spectrum m/z 439[MH⁺].(methylsulfonyl)phenyl]acetamide 97 N-{[4-(3-chlorobenzyl)morpholin-2-Example 91 LC-MS(System A): yl]methyl}-2-[4- Rt 2.09 mins.(methylsulfonyl)phenyl]acetamide Mass Spectrum m/z 437[MH⁺]. 98N-{[4-(3-chlorobenzyl)morpholin-2- Example 91 LC-MS(System A):yl]methyl}-2-[3- Rt 2.11 mins. (methylsulfonyl)phenyl]acetamide MassSpectrum m/z 437[MH⁺]. 99 2-[3-(acetylamino)phenyl]-N-{[4-(4- Example 91LC-MS(System A): fluorobenzyl)morpholin-2- Rt 1.95 mins.yl]methyl}acetamide Mass Spectrum m/z 400[MH⁺]. 1002-[4-(acetylamino)phenyl]-N-{[4-(4- Example 91 LC-MS(System A):fluorobenzyl)morpholin-2- Rt 1.91 mins. yl]methyl}acetamide MassSpectrum m/z 400[MH⁺]. 101 N-{[4-(4-fluorobenzyl)morpholin-2- Example 91LC-MS(System A): yl]methyl}-2-(2-pyrazin-2-yl-1,3- Rt 2.10 mins.thiazol-4-yl)acetamide Mass Spectrum m/z 428[MH⁺]. 102 N-{[4-(2,3-Example 91 LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.36 mins.yl]methyl}-2-[4- Mass Spectrum m/z 471[MH⁺].(methylsulfonyl)phenyl]acetamide 103 2-[3-(acetylamino)phenyl]-N-{[4-Example 91 LC-MS(System A): (2,3-dichlorobenzyl)morpholin-2- Rt 2.30mins. yl]methyl}acetamide Mass Spectrum m/z 450[MH⁺]. 104 N-{[4-(2,3-Example 91 LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.37 mins.yl]methyl}-2-{4- Mass Spectrum m/z 486[MH⁺].[(methylsulfonyl)amino]phenyl} acetamide 105 N-{[4-(2,3- Example 91LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.24 mins.yl]methyl}-2-(4- Mass Spectrum m/z 465[MH⁺].{[(methylamino)carbonyl]amino} phenyl)acetamide 106 N-{[4-(2,3- Example91 LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.44 mins.yl]methyl}-2-(2-pyrazin-2-yl-1,3- Mass Spectrum m/z 478[MH⁺].thiazol-4-yl)acetamide 107 N-({4-[(5-chlorothien-2- Example 91LC-MS(System A): yl)methyl]morpholin-2-yl}methyl)-2- Rt 2.16 mins. [4-Mass Spectrum m/z 443[MH⁺]. (methylsulfonyl)phenyl]acetamide 1082-[3-(acetylamino)phenyl]-N-({4- Example 91 LC-MS(System A):[(5-chlorothien-2- Rt 2.13 mins. yl)methyl]morpholin-2- Mass Spectrumm/z 422[MH⁺]. yl}methyl)acetamide 109 N-({4-[(5-chlorothien-2- Example91 LC-MS(System A): yl)methyl]morpholin-2-yl}methyl)-2- Rt 2.18 mins.{4-[(methylsulfonyl)amino]phenyl} Mass Spectrum m/z 458[MH⁺]. acetamide110 N-({4-[(5-chlorothien-2- Example 91 LC-MS(System A):yl)methyl]morpholin-2-yl}methyl)-2- Rt 2.26 mins.(2-pyrazin-2-yl-1,3-thiazol-4- Mass Spectrum m/z 450[MH⁺]. yl)acetamide111 2-[3-(acetylamino)phenyl]-N-{[4-(3- Example 91 LC-MS(System A):chlorobenzyl)morpholin-2- Rt 2.37 mins. yl]methyl}acetamide MassSpectrum m/z 416[MH⁺]. 112 N-{[4-(3-chlorobenzyl)morpholin-2- Example 91LC-MS(System A): yl]methyl}-2-{4- Rt 2.37 mins.[(methylsulfonyl)amino]phenyl} Mass Spectrum m/z 452[MH⁺]. acetamide 1132-[4-(acetylamino)phenyl]-N-{[4-(3- Example 91 LC-MS(System A):chlorobenzyl)morpholin-2- Rt 2.31 mins. yl]methyl}acetamide MassSpectrum m/z 416[MH⁺]. 114 N-{[4-(3-chlorobenzyl)morpholin-2- Example 91LC-MS(System A): yl]methyl}-2-(4- Rt 2.31 mins.{[(methylamino)carbonyl]amino} Mass Spectrum m/z 431[MH⁺].phenyl)acetamide 115 N-{[4-(3-chlorobenzyl)morpholin-2- Example 91LC-MS(System A): yl]methyl}-2-(2-pyrazin-2-yl-1,3- Rt 2.46 mins.thiazol-4-yl)acetamide Mass Spectrum m/z 444[MH⁺]. 1162-[4-(acetylamino)phenyl]-N-{[4- Example 91 LC-MS(System A):(2,3-dichlorobenzyl)morpholin-2- Rt 2.51 mins. yl]methyl}acetamide MassSpectrum m/z 450[MH⁺]. 117 N-{[4-(2,3- Example 91 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt 2.43 mins. yl]methyl}-2-[3- Mass Spectrumm/z 471[MH⁺]. (methylsulfonyl)phenyl]acetamide 1182-[4-(aminosulfonyl)phenyl]-N-{[4- Example 41 LC-MS(System A):(3,4-dichlorobenzyl)morpholin-2- Rt 2.37 mins. yl]methyl}acetamide MassSpectrum m/z 472[MH⁺]. 119 2-[2-(acetylamino)phenyl]-N-{[4- Exampl(e 41LC-MS(System A): (3,4-dichlorobenzyl)morpholin-2- Rt 2.44 mins.yl]methyl}acetamide Mass Spectrum m/z 450[MH⁺]. 1202-(3-cyanophenyl)-N-{[4-(3,4- Example 41 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt 2.64 mins. yl]methyl}acetamide MassSpectrum m/z 418[MH⁺]. 121 N-{[(2S,5R)-4-(2,5-dichlorobenzyl)- Example24 LC-MS(System A): 5-methylmorpholin-2-yl]methyl}-2- Rt 2.73 mins.phenylacetamide Mass Spectrum m/z 407[MH⁺]. 1222-(4-chlorophenyl)-N-{[(2S,5R)-4- Example 24 LC-MS(System A):(2,5-dichlorobenzyl)-5- Rt 3.02 mins. methylmorpholin-2- Mass Spectrumm/z 441[MH⁺]. yl]methyl}acetamide 123 N-{[4-(3,4- Example 1 LC-MS(SystemA): dichlorobenzyl)morpholin-2- Rt 2.67 mins. yl]methyl}-2-(2- MassSpectrum m/z 411[MH⁺]. fluorophenyl)acetamide 124 N-{[4-(3,4- Example 1LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.75 mins.yl]methyl}-2-(2,3- Mass Spectrum m/z 429[MH⁺]. difluorophenyl)acetamide125 N-{[4-(3,4- Example 1 LC-MS(System A): dichlorobenzyl)morpholin-2-Rt 2.74 mins. yl]methyl}-2-(2,4- Mass Spectrum m/z 429[MH⁺].difluorophenyl)acetamide 126 N-{[4-(3,4- Example 1 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt 2.73 mins. yl]methyl}-2-(2,5- MassSpectrum m/z 429[MH⁺]. difluorophenyl)acetamide 127 3-[2-({[4-(3,4-Example 53 LC-MS(System A): dichlorobenzyl)morpholin-2- Rt mins 2.57.yl]methyl}amino)-2-oxoethyl]-N-(2- Mass Spectrum m/z 494[MH⁺].methoxyethyl)benzamide 128 3-[2-({[4-(3,4- Example 53 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt mins 2.65.yl]methyl}amino)-2-oxoethyl]-N- Mass Spectrum m/z 464[MH⁺].ethylbenzamide 129 3-[2-({[4-(3,4- Example 53 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt 2.61 mins.yl]methyl}amino)-2-oxoethyl]-N,N- Mass Spectrum m/z 464[MH⁺].dimethylbenzamide 130 3-[2-({[4-(3,4- Example 53 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt 2.27 mins.yl]methyl}amino)-2-oxoethyl]-N-[2- Mass Spectrum m/z 507[MH⁺].(dimethylamino)ethyl]benzamide 131 N-{[4-(3,4- Example 53 LC-MS(SystemA): dichlorobenzyl)morpholin-2- Rt 2.25 mins.yl]methyl}-2-{3-[(4-methylpiperazin- Mass Spectrum m/z 519[MH⁺].1-yl)carbonyl]phenyl}acetamide 132 2-(3-aminophenyl)-N-{[4-(3,4- Example56 LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.26 mins.yl]methyl}acetamide Mass Spectrum m/z 408[MH⁺]. 1332-(4-aminophenyl)-N-{[4-(3,4- Example 56 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt 2.29 mins. yl]methyl}acetamide MassSpectrum m/z 408[MH⁺]. 134 N-{[(2S)-4-(3,4- Example 54 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt 2.90 mins.yl]methyl}-2-(5-methyl-2-phenyl- Mass Spectrum m/z 474[MH⁺].1,3-oxazol-4-yl)acetamide hydrochloride

Preparation Name analogous to Characterising Data 1362-[4-(acetylamino)phenyl]-N-{[4- Example LC-MS(System A):(3,4-dichlorobenzyl)morpholin-2- 139 Rt mins 2.49. yl]methyl}acetamideMass Spectrum m/z 450[MH⁺]. 137 N-{4-[2-({[4-(3,4- Example LC-MS(SystemA): dichlorobenzyl)morpholin-2- 139 Rt 2.77 mins. yl]methyl}amino)-2-Mass Spectrum m/z 478[MH⁺]. oxoethyl]phenyl}-2- methylpropanamide 138N-{3-[2-({[4-(3,4- Example LC-MS(System A): dichlorobenzyl)morpholin-2-139 Rt 2.77 mins. yl]methyl}amino)-2- Mass Spectrum m/z 478[MH⁺].oxoethyl]phenyl}-2- methylpropanamide

Example 139N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{3-[(methylsulfonyl)amino]phenyl}acetamide

Methanesulphonylchloride (0.022 ml) was added to a stirred solution ofExample 132 (0.1149) in dichloromethane (5 ml), and stirring wascontinued at 22° C. for 2 h. After leaving to stand for a further 112 h,tris-(2-aminoethyl)amine polystyrene resin (0.026 g) was added andstirring continued for a further 2 h. N,N-Dimethylformamide (1 ml) wasadded and the mixture applied to a 10 g ion exchange cartridge (IsoluteSCX, pre-conditioned with methanol). Elution with methanol (3 columnvolumes) followed by 10% 0.880 ammonia in methanol (2 column volumes)and evaporation of the first basic fraction gave a residue, which wasre-dissolved in dichloromethane, treated with polystyrenemethylisocyanate resin (3.85 mmol/g, 0.026 g), and left to stand for 1h. The mixture was applied to a log silica gel cartridge (Varian BondElut, pre-conditioned with dichloromethane), and eluted with 1 columnvolume each of dichloromethane, chloroform, ether, ethyl acetate,acetone, acetonitrile and methanol. The appropriate fraction wasevaporated in vacuo to give the title compound as a colourless gum(0.115 g).

LC/MS (system A) R_(t) 2.65 min Mass Spectrum m/z 486 [MH⁺]

Examples 140-150

Preparation Name analogous to Characterising Data 140N-{[(2S,5R)-4-(3,4-dichlorobenzyl)- Example 24 LC-MS(System A):5-methylmorpholin-2-yl]methyl}-2- Rt 2.93 mins.(5-methyl-2-phenyl-1,3-oxazol-4- Mass Spectrum m/z 488[MH⁺].yl)acetamide Normal Phase Analytical HPLC RT 14.31 mins. 141 N-{[4-(3,4-Example LC-MS(System A): dichlorobenzyl)morpholin-2- 139 Rt 2.57 mins.yl]methyl}-2-{4- Mass Spectrum m/z 486[MH⁺].[(methylsulfonyl)amino]phenyl} acetamide 142 N-{3-[2-({[4-(3,4- ExampleLC-MS(System A): dichlorobenzyl)morpholin-2- 136 Rt 2.29 mins.yl]methyl}amino)-2- Mass Spectrum m/z 493[MH⁺]. oxoethyl]phenyl}-2-(dimethylamino)acetamide 143 2-{4- Example LC-MS(System A):[bis(methylsulfonyl)amino]phenyl}- 139 Rt 2.62 mins. N-{[4-(3,4- MassSpectrum m/z 564, dichlorobenzyl)morpholin-2- 566[MH⁺].yl]methyl}acetamide 144 N-{[4-(3,4- Example 41 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt 3.05 mins.yl]methyl}-2-(5-methyl-2-phenyl- Mass Spectrum m/z 490[MH⁺].1,3-thiazol-4-yl)acetamide 145 N-{[4-(3,4- Example 41 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt 2.60 mins.yl]methyl}-2-(5-methyl-2-pyrazin-2- Mass Spectrum m/z 492[MH⁺].yl-1,3-thiazol-4-yl)acetamide 146 N-{[4-(3,4- Example 56 LC-MS(SystemA): dichlorobenzyl)morpholin-2- Rt 2.61 mins. yl]methyl}-2-[3- MassSpectrum m/z 471[MH⁺]. methylsulfonyl)phenyl]acetamide 147 N-{[4-(3,4-Example 41 LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.6 mins.yl]methyl}-2-[4-(methylsulfonyl)-2- Mass Spectrum m/z 518[MH⁺].nitrophenyl]acetamide 148 N-{[4-(3,4- Example 41 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt 2.52 mins. yl]methyl}-2-(2- Mass Spectrumm/z 409[MH⁺]. hydroxyphenyl)acetamide 149 N-{[4-(3,4- Example 41LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.78 mins.yl]methyl}-2-(2-phenyl-1,3-oxazol- Mass Spectrum m/z 460[MH⁺].4-yl)acetamide 150 N-{[4-(3,4- Example LC-MS(System A):dichlorobenzyl)morpholin-2- 151 Rt 2.73 mins. yl]methyl}2-{4- MassSpectrum m/z 500[MH⁺]. [methyl(methylsulfonyl)amino] phenyl}acetamide

Example 151N-{[4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}-2-{3-[methyl(methylsulfonyl)amino]phenyl}acetamide

Potassium carbonate (0.035 g) and iodomethane (0.015 ml) were added to astirred solution of Example 139 (0.115 g) in acetone (1 ml), andstirring was continued at 22° C. for 72 h before a further portion ofiodomethane (0.003 ml) was added. After stirring for a further 24 h,more iodomethane (0.003 ml) and potassium carbonate (0.007 g)were:.added, and the mixture stirred for a further 48 h. The mixture wasapplied in two equal portions to two ion exchange cartridges (2 gIsolute SCX, pre-conditioned with methanol). Elution with methanol (3column volumes) followed by 10% 0.880 ammonia in methanol (2 columnvolumes), and evaporation of the first basic fraction from each elutionin vacuo gave the title compound as a pale yellow gum (0.038 g).

LC/MS (system A) R_(t) 2.73 min Mass Spectrum m/z 500 [MH⁺]

Examples 152-157

Preparation Name analogous to Characterising Data 152 N-{[(2S)-4-(3,4-Example 44 LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.18 mins.yl]methyl}-4- Mass Spectrum m/z 423[MH⁺] (methylsulfonyl)butanamide 153N-{[4-(3,4- Example 41 LC-MS(System A): dichlorobenzyl)morpholin-2- Rt2.87 mins. yl]methyl}-2-[5-methyl-2-(5- Mass Spectrum m/z 494[MH⁺].methylthien-2-yl)-1,3-oxazol-4- yl]acetamide 154 2-[2-amino-4- Example41 LC-MS(System A): (methylsulfonyl)phenyl]-N-{[4-(3,4- Rt 2.36 mins.dichlorobenzyl)morpholin-2- Mass Spectrum m/z 486[MH⁺].yl]methyl}acetamide 155 N-{[4-(3,4- Example 41 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt 2.79 mins.yl]methyl}-2-(5-methyl-2-thien-2-yl- Mass Spectrum m/z 480[MH⁺].1,3-oxazol-4-yl]acetamide 156 N-{[4-(3,4- Example 41 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt 2.64 mins.yl]methyl}-2-[2-(2-furyl)-5-methyl- Mass Spectrum m/z 464[MH⁺].1,3-oxazol-4-yl]acetamide 157 N-{[4-(3,4- Example 1 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt 2.30 mins. yl]methyl}pent-4-ynamide MassSpectrum m/z 355[MH⁺].

Example 158N-{[(2S)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-(5-methyl-2-pyridin-3-yl-1,3-oxazol-4-yl)acetamideCompound with formic acid (1:1)

N,N′-carbonyldiimidazole (15 mg) was added to a stirred solution ofIntermediate 34 (20 mg) at 22° C. under nitrogen, and the mixture wasstirred at 22° C. for 1 h. Intermediate 9 (26 mg) was added and themixture stirred at 22° C. for 24 h. The mixture was applied directly toa sulphonic acid ion exchange cartridge (Isolute SCX, 2 g) and elutedwith methanol followed by 10% 0.880 ammonia in methanol. Evaporation ofthe methanolic ammonia fraction gave a gum (50 mg) which was furtherpurified by solid phase extraction on silica gel (1 g Varian Bondelutcartridge), eluting with chloroform, ether, ethyl acetate, acetone andmethanol to give a gum (38 mg). The gum was partitioned betweendichloromethane and water, and the organic layer treated withpolystyrene methylisocyanate resin (Argonaut, 95 mg, 1.6 mmol/g). Aftershaking for 4 h the resin was filtered off and the filtrate evaporatedto give a gum (29 mg), which was further purified by chromatography onsilica gel, eluting with dichloromethane: ethanol: 0.880 ammonia100:0:0-95:5:0.5, followed by mass directed preparative HPLC to give thetitle compound (7.6 mg).

LC-MS (System A) Rt 2.48 min. Mass Spectrum m/z 475 (MH⁺].

Examples 159-161

Preparation Name analogous to Characterising Data 159 N-{[(2S)-4-(3,4-Example LC-MS(System A): dichlorobenzyl)morpholin-2- 158 Rt 2.66 mins.yl]methyl}-2-(2-isopropyl-5-methyl- Mass Spectrum m/z 440[MH⁺].1,3-oxazol-4-yl)acetamide 160 N-{[(2S)-4-(3,4- Example LC-MS(System A):dichlorobenzyl)morpholin-2- 162 Rt 2.50 mins. yl]methyl}-2-{4- MassSpectrum m/z 486[MH⁺]. [(methylamino)sulfonyl]phenyl} acetamide 161N-{[(2S)-4-(3,4- Example LC-MS(System A): dichlorobenzyl)morpholin-2-162 Rt 2.58 mins. yl]methyl}-2-{4- Mass Spectrum m/z 500[MH⁺].[(ethylamino)sulfonyl]phenyl} acetamide

Example 1622-[3-(Aminosulfonyl)phenyl]-N-{[(2S)-4-(3,dichlorobenzyl)morpholin-2-yl]methyl}acetamide

To a stirred solution of Intermediate 40 (0.021 g) inN,N-dimethylformamide (1 ml) was added 1-hydroxybenzotriazole (0.015 g),N,N-diisopropylethylamine (0.028 ml) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.025 g)followed by a solution of Intermediate 9 (0.023 g) inN,N-dimethylformamide (1 ml). The mixture was stirred for 4 h at 22° C.,and applied to an ion exchange cartridge (2 g Isolute SCX,pre-conditioned with methanol). Elution with methanol (3 column volumes)followed 10% 0.880 ammonia in methanol (2 column volumes) andevaporation of the first basic fraction in vacuo gave a residue whichwas re-dissolved in dichloromethane and applied to a silica gelcartridge (2g Varian Bond Elut, pre-conditioned with dichloromethane).Elution with dichloromethane, chloroform, ether, ethyl acetate, acetone,acetonitrile and methanol (1 column volume each), and evaporation of theproduct containing fractions in vacuo gave the title compound as ayellow gum (0.026 g).

LCMS (System A) R_(t) 2.38 min Mass Spectrum m/z 472 [MH⁺].

Chiral Analytical HPLC on Chiralcel OD-H column, detection at 230 nm,eluent 25% EtOH/n-heptane, Rt 12.4 min.

Examples 162A-213

Preparation Name analogous to Characterising Data   162A2-[3-(Aminosulfonyl)phenyl]-N-{[4- Example LC-MS(System A):(3,4-dichlorobenzyl)morpholin-2- 162 (from Rt 2.36 mins.yl]methyl}acetamide Intermediate Mass Spectrum m/z 472[MH⁺]. 1) ChiralAnalytical HPLC on Chiralcel OD-H column, detection at 230 nm, eluent25% EtOH/n-heptane, Rt 12.5 min and 10.3 min. 163 2-{3- ExampleLC-MS(System A): [(cyclopropylamino)sulfonyl]phenyl}- 162 Rt 2.66 mins.N-{[(2S)-4-(3,4- Mass Spectrum m/z 512[MH⁺]. dichlorobenzyl)morpholin-2-yl]methyl}acetamide 164 N-{[(2S)-4-(3,4- Example LC-MS(System A):dicholorobenzyl)morpholin-2- 162 Rt 2.62 mins. yl]methyl}-2-{3- MassSpectrum m/z 500[MH⁺]. [(ethylamino)sulfonyl]phenyl} acetamide 165N-{[(2S)-4-(3,4- Example LC-MS(System A): dichlorobenzyl)morpholin-2-162 Rt 2.50 mins. yl]methyl}-2-{3- Mass Spectrum m/z 486[MH⁺].[(methylamino)sulfonyl]phenyl} acetamide 166 N-{[(2S)-4-(3,4- Example 41LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.41 mins.yl]methyl}-2-(5-methyl-2- Mass Spectrum m/z 483[MH⁺].morpholin-4-yl-1,3-oxazol-4- yl)acetamide 1672-[4-(aminosulfonyl)phenyl]-N-{[4- Example LC-MS(System A):(3,4-dichlorobenzyl)morpholin-2- 162 Rt 2.34 mins. yl]methyl}acetamideMass Spectrum m/z 472[MH⁺]. 168 2-{4- Example LC-MS(System A):[(cyclopropylamino)sulfonyl]phenyl}- 162 Rt 2.65 mins. N-{[4-(3,4- MassSpectrum m/z 512[MH⁺]. dichlorobenzyl)morpholin-2- yl]methyl}acetamide169 methyl 2-[2-({[4-(3,4- Example 86 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt 2.76 mins.yl]methyl}amino)-2-oxoethyl]-2H- Mass Spectrum m/z 492[MH⁺].1,2,3-benzotriazole-5-carboxylate 170 N-{[4-(3,4- Example 86LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.59 mins.yl]methyl}-2-(1H-pyrrolo[2,3- Mass Spectrum m/z 433[MH⁺].b]pyridin-1-yl)acetamide 171 N-{[4-(3,4- Example 86 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt 2.48 mins.yl]methyl}-2-(5-pyridin-2-yl-2H- Mass Spectrum m/z 462[MH⁺].tetraazol-2-yl)acetamide 172 N-{[4-(3,4- Example 86 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt 2.45 mins.yl]methyl}-2-(5-pyridin-3-yl-2H- Mass Spectrum m/z 462[MH⁺].tetraazol-2-yl)acetamide 173 N-{[4-(3,4- Example 86 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt 2.77 mins.yl]methyl}-2-[5-(3-formylphenyl)- Mass Spectrum m/z 489[MH⁺].2H-tetraazol-2-yl]acetamide 174 methyl 1-[2-({[4-(3,4- Example 86LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.66 mins.yl]methyl}amino)-2-oxoethyl]-1H- Mass Spectrum m/z 492[MH⁺].1,2,3-benzotriazole-5-carboxylate, compound with methyl 1-[2-({[4-(3,4-dichlorobenzyl)morpholin-2- yl]methyl}amino)-2-oxoethyl]-1H-1,2,3-benzotriazole-6-carboxylate (1:1) 175 N-{[(2S)-4-(3,4- Example 41LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.65 mins.yl]methyl}-2-[2-(2-furyl)-5-methyl- Mass Spectrum m/z 464[MH⁺].1,3-oxazol-4-yl]acetamide 176 N-{[(2S)-4-(3,4- Example 41 LC-MS(SystemA): dichlorobenzyl)morpholin-2- Rt 2.80 mins.yl]methyl}-2-(5-methyl-2-thien-2-yl- Mass Spectrum m/z 478[MH⁺].1,3-oxazol-4-yl)acetamide 177 N-({(2S)-4-[(5-chlorothien-2- Example 41LC-MS(System A): yl)methyl]morpholin-2-yl}methyl)-2- Rt 2.75 mins.(5-methyl-2-phenyl-1,3-oxazol-4- Mass Spectrum m/z 446[MH⁺].yl)acetamide 178 N-{[(2S)-4-(2,3- Example 41 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt 2.97 mins.yl]methyl}-2-(5-methyl-2-phenyl- Mass Spectrum m/z 474[MH⁺].1,3-oxazol-4-yl)acetamide 179 N-({(2S)-4-[(5-chlorothien-2- Example 41LC-MS(System A): yl)methyl]morpholin-2-yl}methyl)-2- Rt 2.82 mins.[2-(4-fluorophenyl)-5-methyl-1,3- Mass Spectrum m/z 484[MH⁺].oxazol-4-yl]acetamide 180 N-{[(2S)-4-(4- Example 41 LC-MS(System A):fluorobenzyl)morpholin-2- Rt 2.54 mins.yl]methyl}-2-[2-(4-fluorophenyl)-5- Mass Spectrum m/z 442[MH⁺].methyl-1,3-oxazol-4-yl]acetamide 181 N-{[(2S)-4-(2,3- Example 54LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.97 mins.yl]methyl}-2-[2-(4-fluorophenyl)-5- Mass Spectrum m/z 492[MH⁺].methyl-1,3-oxazol-4-yl]acetamide 182 N-({(2S)-4-[(5-chlorothien-2-Example 41 LC-MS(System A): yl)methyl]morpholin-2-yl}methyl)-2- Rt 2.64mins. (2-phenyl-1,3-oxazol-4- Mass Spectrum m/z 432[MH⁺]. yl)acetamide183 N-{[(2S)-4-(4- Example 41 LC-MS(System A): fluorobenzyl)morpholin-2-Rt 2.39 mins. yl]methyl}-2-(2-phenyl-1,3-oxazol- Mass Spectrum m/z410[MH⁺]. 4-yl)acetamide 184 N-{[(2S)-4-(2,3- Example 41 LC-MS(SystemA): dichlorobenzyl)morpholin-2- Rt 2.86 mins.yl]methyl}-2-(2-phenyl-1,3-oxazol- Mass Spectrum m/z 460[MH⁺].4-yl)acetamide 185 N-{[(2S)-4-(3,4- Example 41 LC-MS(System A):difluorobenzyl)morpholin-2- Rt 2.59 mins.yl]methyl}-2-(5-methyl-2-phenyl- Mass Spectrum m/z 442[MH⁺].1,3-oxazol-4-yl)acetamide 186 N-{[(2S)-4-(3- Example 41 LC-MS(System A):chlorobenzyl)morpholin-2- Rt 2.63 mins. yl]methyl}-2-(5-methyl-2-phenyl-Mass Spectrum m/z 440[MH⁺]. 1,3-oxazol-4-yl)acetamide 187N-{[(2S)-4-(3,4- Example 41 LC-MS(System A): difluorobenzyl)morpholin-2-Rt 2.64 mins. yl]methyl}-2-[2-(4-fluorophenyl)-5- Mass Spectrum m/z460[MH⁺]. methyl-1,3-oxazol-4-yl]acetamide 188 N-{[((2S)-4-(3- Example41 LC-MS(System A): chlorobenzyl)morpholin-2- Rt 2.68 mins.yl]methyl}-2-[2-(4-fluorophenyl)-5- Mass Spectrum m/z 458[MH⁺].methyl-1,3-oxazol-4-yl]acetamide 189 N-{[(2S)-4-(3,4- Example 41LC-MS(System A): difluorobenzyl)morpholin-2- Rt 2.50 mins.yl]methyl}-2-(2-phenyl-1,3-oxazol- Mass Spectrum m/z 428[MH⁺].4-yl)acetamide 190 N-{[(2S)-4-(3- Example 41 LC-MS(System A):chlorobenzyl)morpholin-2- Rt 2.54 mins.yl]methyl}-2-(2-phenyl-1,3-oxazol- Mass Spectrum m/z 426[MH⁺].4-yl)acetamide 191 N-{[(2S)-4-(3,4- Example 54 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt 2.90 mins.yl]methyl}-2-[2-(4-fluorophenyl)-5- Mass Spectrum m/z 492[MH⁺].methyl-1,3-oxazol-4-yl]acetamide 192 N-{[(2S)-4-(3,4- Example 41LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.81 mins.yl]methyl}-2-(2-phenyl-1,3-oxazol- Mass Spectrum m/z 460[MH⁺].4-yl)acetamide 193 N-cyclopropyl-3-[2-({[(2S)-4-(2,3- Example 41LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.45 mins.yl]methyl}amino)-2- Mass Spectrum m/z 476[MH⁺]. oxoethyl]benzamide 1943-{2-[({(2S)-4-[(5-chlorothien-2- Example 41 LC-MS(System A):yl)methyl]morpholin-2- Rt 2.28 mins. yl}methyl)amino]-2-oxoethyl}-N-Mass Spectrum m/z 447[MH⁺]. cyclopropylbenzamide 195N-cyclopropyl-3-[2-({[(2S)-4-(4- Example 41 LC-MS(System A):fluorobenzyl)morpholin-2- Rt 2.11 mins. yl]methyl}amino)-2- MassSpectrum m/z 425[MH⁺]. oxoethyl]benzamide 196 3-[2-({[(2S)-4-(3- Example41 LC-MS(System A): chlorobenzyl)morpholin-2- Rt 2.24 mins.yl]methyl}amino)-2-oxoethyl]-N- Mass Spectrum m/z 442[MH⁺].cyclopropylbenzamide 197 N-cyclopropyl-3-[2-({[(2S)-4-(3,4- Example 41LC-MS(System A): difluorobenzyl)morpholin-2- Rt 2.12 mins.yl]methyl}amino)-2- Mass Spectrum m/z 444[MH⁺]. oxoethyl]benzamide 198N-cyclopropyl-3-[2-({[(2S)-4-(3,4- Example 41 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt 2.46 mins. yl]methyl}amino)-2- MassSpectrum m/z 476[MH⁺]. oxoethyl]benzamide 199 N-{[(2S)-4-(2,3- Example41 LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.90 mins.yl]methyl}-2-(5-phenyl-2H- Mass Spectrum m/z 461[MH⁺].tetraazol-2-yl)acetamide 200 N-{[(2S)4-(4- Example 41 LC-MS(System A):fluorobenzyl)morpholin-2- Rt 2.42 mins. yl]methyl}-2-(5-phenyl-2H- MassSpectrum m/z 410[MH⁺]. tetraazol-2-yl)acetamide 201 N-{[(2S)-4-(3-Example 41 LC-MS(System A): chlorobenzyl)morpholin-2- Rt 2.57 mins.yl]methyl}-2-(5-phenyl-2H- Mass Spectrum m/z 427[MH⁺].tetraazol-2-yl)acetamide 202 N-{[(2S)-4-(3,4- Example 41 LC-MS(SystemA): difluorobenzyl)morpholin-2- Rt 2.53 mins. yl]methyl}-2-(5-phenyl-2H-Mass Spectrum m/z 429[MH⁺]. tetraazol-2-yl)acetamide 203N-{[(2S)-4-(3,4- Example 41 LC-MS(System A): dichlorobenzyl)morpholin-2-Rt 2.95 mins. yl]methyl}-2-[5-methyl-2-(3- Mass Spectrum m/z 494[MH⁺].methylthien-2-yl)-1,3-oxazol-4- yl]acetamide 204 N-{[(2S)-4-(3,4-Example 41 LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.63 mins.yl]methyl}-2-[2-(1,3-dimethyl-1H- Mass Spectrum m/z 492 [MH⁺].pyrazol-5-yl)-5-methyl-1,3-oxazol- 4-yl]acetamide 2052-[2-(3-chlorothien-2-yl)-5-methyl- Example 41 LC-MS(System A):1,3-oxazol-4-yl]-N-{[(2S)-4-(3,4- Rt 2.93 mins.dichlorobenzyl)morpholin-2- Mass Spectrum m/z yl]methyl}acetamide514,516[MH⁺]. 206 N-({(2S)-4-[(5-chlorothien-2- Example 41 LC-MS(SystemA): yl)methyl]morpholin-2-yl}methyl)-2- Rt 2.69 mins.(5-phenyl-2H-tetraazol-2- Mass Spectrum m/z 433[MH⁺]. yl)acetamide 207N-{[(2S)-4-(3- Example 54 LC-MS(System A): cyanobenzyl)morpholin-2- Rt2.55 mins. yl]methyl}-2-[2-(4-fluorophenyl)-5- Mass Spectrum m/z449[MH⁺]. methyl-1,3-oxazol-4-yl]acetamide 208N-{[(2S)-4-(2,1,3-benzoxadiazol-5- Example 54 LC-MS(System A):ylmethyl)morpholin-2-yl]methyl}-2- Rt 2.80 mins.[2-(4-fluorophenyl)-5-methyl-1,3- Mass Spectrum m/z 466[MH⁺].oxazol-4-yl]acetamide 209 2-[2-(4-fluorophenyl)-5-methyl-1,3- Example 54LC-MS(System A): oxazol-4-yl]-N-{[(2S)-4-(2,3,4- Rt 2.78 mins.trifluorobenzyl)morpholin-2- Mass Spectrum m/z 478[MH⁺].yl]methyl}acetamide 210 2-[8 2-(4-fluorophenyl)-5-methyl-1,3- Example 54LC-MS(System A): oxazol-4-yl]-N-({(2S)-4-[4-fluoro-3- Rt 2.89 mins.(trifluoromethyl)benzyl]morpholin- Mass Spectrum m/z 510[MH⁺].2-yl}methyl)acetamide 211 N-{[(2S)-4-(3,4- Example 56 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt 2.62 mins. yl]methyl}-2-{5-methyl-2-[4-Mass Spectrum m/z 552[MH⁺]. (methylsulfonyl)phenyl]-1,3-oxazol-4-yl}acetamide 212 N-{[(2S)-4-(3,4- Example 41 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt 2.97 mins.yl]methyl}-2-(5-methyl-2-phenyl- Mass Spectrum m/z 490[MH⁺].1,3-thiazol-4-yl)acetamide 213 N-{[(2S)-4-(3,4- Example 41 LC-MS(SystemA): dichlorobenzyl)morpholin-2- Rt 2.51 mins.yl]methyl}-2-(5-methyl-2-pyrazin-2- Mass Spectrum m/z 492[MH⁺].yl-1,3-thiazol-4-yl)acetamide

A mixture of Intermediate 28 (0.049), 3-(4-chlorophenyl)propanal (0.026g) and acetic acid (0.02 ml) in dichloromethane (4 ml) was treated withsodium triacetoxyborohydride (0.080 g). The mixture was stirred at 20°C. for 72 h. The mixture was partitioned between chloroform (6 ml) andsaturated aqueous sodium hydrogen carbonate (6ml). The phases wereseparated and the organic phase applied to an ion exchange cartridge (2g Isolute SCX, prewashed with methanol). The SCX cartridge was elutedwith methanol (10 ml) followed by 10% 0.880 ammonia in methanol (10 ml)and the appropriate fractions were concentrated in vacuo to give thetitle compound as a colourless gum (0.055 g).

LCMS (system A) R_(t) 2.65 min Mass Spectrum m/z 486 [MH⁺].

Examples 215-219

Preparation Name analogous to Characterising Data 2152-(2-cyclopropyl-5-methyl-1,3- Example LC-MS(System A):oxazol-4-yl)-N-{[(2S)-4-(3,4- 158 Rt 2.48 mins.dichlorobenzyl)morpholin-2- Mass Spectrum m/z 438[MH⁺].yl]methyl}acetamide 216 N-{[(2S)-4-(3,4- Example LC-MS(System A):dichlorobenzyl)morpholin-2- 158 Rt 2.70 mins.yl]methyl}-2-(2-isobutyl-5-methyl- Mass Spectrum m/z 454[MH⁺].1,3-oxazol-4-yl)acetamide 217 N-{[(2S)-4-(3,4- Example LC-MS(System A):dichlorobenzyl)morpholin-2- 158 Rt 2.71 mins.yl]methyl}-2-[5-methyl-2-(2- Mass Spectrum m/z 452[MH⁺].methylprop-1-enyl)-1,3-oxazol-4- yl]acetamide 218 N-{[(2S)-4-(3,4-Example LC-MS(System A): dichlorobenzyl)morpholin-2- 158 Rt 2.38 mins.yl]methyl}-2-(5-methyl-2-pyridin-2- Mass Spectrum m/z 475[MH⁺].yl-1,3-oxazol-4-yl)acetamide compound with formic acid (1:1) 219N-{[(2S)-4-(3,4- Example 41 LC-MS(System A): dichlorobenzyl)morpholin-2-Rt 2.85 mins. yl]methyl}-2-[5-(4-fluorophenyl)- Mass Spectrum m/z479[MH⁺]. 2H-tetraazol-2-yl]acetamide

Example 220N-{[(2S)-4-(3,4-Dichlorobenzyl)morpholin-2-yl]methyl}-2-[5-(4-fluorophenyl)-1,2,4oxadiazol-3-yl]acetamide

A mixture of Intermediate 38 (0.024 g), Intermediate 9(0.025 g), and1-methyl-2-pyrrolidinone (1 drop) was subjected was subjected toirradiation in a 600W microwave oven on full power for 4 mins. Thereaction mixture was dissolved in methanol and applied to an ionexchange cartridge (2 g Isolute SCX, pre-conditioned with methanol).Elution with methanol (3 column volumes) followed 10% 0.880 ammonia inmethanol (2 column volumes) and evaporation of the first basic fractionin vacuo gave the crude product. Purification by Biotage flash columnchromatography on silica gel (8 g cartridge), eluting with 100:8:1dichloromethane/ethanol/0.880 ammonia, gave the title compound as awhite solid (0.025 g).

LCMS (System A) R_(t) 2.85 min Mass Spectrum m/z 479, 481 [MH+]

Examples 221-224

Preparation Name analogous to Characterising Data 221N-{[(2S)-4-(2,1,3-benzothiadiazol- Example 54 LC-MS(System A):5-ylmethyl)morpholin-2-yl]methyl}- Rt 2.51 mins.2-[2-(4-fluorophenyl)-5-methyl-1,3- Mass Spectrum m/z 482[MH⁺].oxazol-4-yl]acetamide 222 4-{4-[2-({[(2S)-4-(3,4- Example 56LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 2.50 mins.yl]methyl}amino)-2-oxoethyl]-5- Mass Spectrum m/z 545[MH⁺].methyl-1,3-oxazol-2-yl}-N,N- dimethylbenzamide 2232-{2-[4-(acetylamino)phenyl]-5- Example 56 LC-MS(System A):methyl-1,3-oxazol-4-yl}-N-{[(2S)-4- Rt 2.54 mins.(3,4-dichlorobenzyl)morpholin-2- Mass Spectrum m/z 531[MH⁺].yl]methyl}acetamide 224 N-{[(2S)-4-(1,2,3-benzothiadiazol- ExampleLC-MS(System A): 6-ylmethyl)morpholin-2-yl]methyl}- 214 Rt 2.59 mins.2-[2-(4-fluorophenyl)-5-methyl-1,3- Mass Spectrum m/z 482[MH⁺].oxazol-4-yl]acetamide

Example 225N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}pentanamide

A solution of Intermediate 9 (0.028 g) in dichloromethane (2 ml)containing a suspension of polyvinyl pyridine (0.1 g) was treated withvaleryl chloride (0.018 ml), and the mixture was shaken at 20° C. for 16h. Tris(2-aminoethyl)amine polystyrene scavenger resin (ArgonautTechnologies, 4.46 mmol/g; 0.067 g) was added, and the mixture wasshaken at 20° C. for 2 h. The mixture was filtered and the filtrateapplied directly to a silica gel cartridge (1 g Varian Bond Elut).Elution with chloroform, ether, and ethyl acetate gave the titlecompound 0.0225 g).

LC-MS (System A) Rt 2.43 mins. Mass Spectrum m/z 359 [MH⁺].

Examples 226-238

Preparation Name analogous to Characterising Data 226 N-{[(2S)-4-(3,4-Example LC-MS(System A): dichlorobenzyl)morpholin-2- 225 Rt 2.58 mins.yl]methyl}-4-methylpentanamide Mass Spectrum m/z 373[MH⁺]. 227N-({4-[3-(3,4- Example 1 LC-MS(System A):dichlorophenyl)propyl]morpholin-2- Rt 2.76 mins.yl}methyl)-2-phenoxyacetamide Mass Spectrum m/z 437[MH⁺]. 2282-cyclohexyl-N-{[4-(3,4- Example 1 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt 2.81 mins. yl]methyl}acetamide MassSpectrum m/z 399[MH⁺]. trifluoroacetate 2292-(4-chlorophenyl)-N-{[4-(3,4- Example 1 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt 3.00 mins. yl]methyl}propanamide MassSpectrum m/z 443[MH⁺]. 230 N-{[4-(3,4- Example 1 LC-MS(System A):dichlorobenzyl)morpholin-2- Rt 2.39 mins. yl]methyl}-2-(1,1- MassSpectrum m/z 450[MH⁺]. dioxidothiomorpholin-4- yl)acetamide 2312-[2-(4-fluorophenyl)-5-methyl-1,3- Example 54 LC-MS(System A):oxazol-4-yl]-N-({(2S)-4-[2-(4- Rt 2.58 mins. fluorophenyl)-2- MassSpectrum m/z 470[MH⁺]. oxoethyl]morpholin-2- yl}methyl)acetamide 232N-({(2S)-4-[(3-chloro-1-benzothien- Example 54 LC-MS(System A):2-yl)methyl]morpholin-2-yl}methyl)- Rt 3.46 mins.2-[2-(4-fluorophenyl)-5-methyl-1,3- Mass Spectrum m/z 514[MH⁺].oxazol-4-yl]acetamide 233 2-[2-(4-fluorophenyl)-5-methyl-1,3- Example 54LC-MS(System A): oxazol-4-yl]-N-{[(2S)-4-(2- Rt 2.37 mins.methylprop-2-enyl)morpholin-2- Mass Spectrum m/z 488[MH⁺].yl]methyl}acetamide 234 2-[2-(4-fluorophenyl)-5-methyl-1,3- Example 54LC-MS(System A): oxazol-4-yl]-N-{[(2S)-4-(1- Rt 2.48 mins.phenylethyl)morpholin-2- Mass Spectrum m/z 438[MH⁺]. yl]methyl}acetamide235 N-{[(2S)-4-(3-cyano-4- Example 54 LC-MS(System A):fluorobenzyl)morpholin-2- Rt 2.59 mins.yl]methyl}-2-[2-(4-fluorophenyl)-5- Mass Spectrum m/z 467[MH⁺].methyl-1,3-oxazol-4-yl]acetamide 236 N-{[(2S)-4-(3,4- Example 41LC-MS(System A): dichlorobenzyl)morpholin-2- Rt 3.16 mins.yl]methyl}-2-[2-(4-fluorophenyl)-5- Mass Spectrum m/z 520[MH⁺].isopropyl-1,3-oxazol-4- yl]acetamide 237 N-{[(2S)-4-(3,4- ExampleLC-MS(System A): dichlorobenzyl)morpholin-2- 225 Rt 2.22 mins.yl]methyl}cyclopropane Mass Spectrum m/z 343[MH⁺]. carboxamide 238N-({(2S)-4-[2-(3- Example 54 LC-MS(System A):chlorophenoxy)ethyl]morpholin-2- Rt 2.72 mins.yl}methyl)-2-[2-(4-fluorophenyl)-5- Mass Spectrum m/z 488[MH⁺].methyl-1,3-oxazol-4-yl]acetamide

Example 239N-{[(2S)-4-(3,4-dichlorobenzoyl)morpholin-2-yl]methyl}-2-[2-(4-fluorophenyl)-5-methyl-1,3-oxazol-4-yl]acetamide

A mixture of Intermediate 12 (0.015 g), 1-hydroxybenzotriazole (0.0097g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.012g) and N,N-diisopropylethylamine (0.027 ml) in N,N-dimethylformamide (2ml) was stirred at 20° C. for 10 min. The mixture was treated withIntermediate 31 (0.023 g) and stirred at 20° C. for 96 h. The mixturewas applied sequentially to a sulphonic acid ion exchange cartridge (1 gSCX, prewashed with methanol) and Isolute^(R) aminopropyl solid phaseextraction cartridge (1 g), eluting both cartridges with methanol (5ml). The solvent was removed in vacuo to give the title compound as ayellow gum (0.032 g).

LCMS (system A) R_(t) 3.3 min Mass Spectrum m/z 506 [MH⁺]

Example 240 tert-butyl4-[3-({[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}amino)-3-oxopropyl]piperidine-1-carboxylate

Example 240 was prepared in an analogous manner to Example 44 from3-C1-(tert-butoxycarbonyl)piperidin-4-yl]propanoic acid.

LC-MS (System A) Rt 2.89 mins Mass Spectrum m/z 514 [MH⁺]

Biological Data

The compounds of the Examples were tested in the CCR-3 binding and/oreosinophil chemotaxis assays (assays (a) and (b)) and results wereobtained as follows: CCR-3 Binding CCR-3 Eosinophil Example Assay(pIC50) Chemotaxis Assay (fpKi) 2 6.51 3 7.15 5 7.11 6 6.86 7 7.82 86.84 10 6.80 12 6.82 13 6.62 14 6.47 17 6.24 19 6.08 22 6.96 25 7.22 277.39 31 6.29 32 7.32 35 6.81 37 7.97 38 7.00 39 8.31 41 7.99 42 9.32 448.17 45 7.88 46 7.14 49 8.07 53 8.39 54 7.62 7.96 55 6.40 162 7.9 8.2

Compounds of Examples 1, 4, 9, 11, 15-16, 18, 20-21, 23-24, 26, 28-30,33-34, 48, 50-52, 56-161 and 163-240 were also tested in CCR-3 bindingassay d achieved a pIC50 value greater than 5.0.

Throughout the specification and the claims which follow, unless thecontext requires otherwise, the word ‘comprise’, and variations such as‘comprises’ and ‘comprising’, will be understood to imply the inclusionof a stated integer or step or group of integers but not to theexclusion of any other integer or step or group of integers or steps.

1. A compound of formula (I):

wherein: R¹ represents C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₂₋₆ alkynyl-Y¹—, aryl-Y¹—, heteroaryl-Y¹—, aryl-(O)_(t)-aryl-Y¹—, aryl-(O)_(t)-heteroaryl-Y¹—, heteroaryl-(O)_(t)-aryl-Y¹—, heteroaryl-(O)_(t)-heteroaryl-Y¹—, C₂₋₆ alkenyl-Y¹—, aryl-O—Y¹—, heteroaryl-O—Y¹—, C₁₋₆ alkyl-SO₂—Y¹—, M-Y¹—, J²-Y¹—, —CN or C₃₋₈ cycloalkyl-Y¹— or C₃₋₈ cycloalkenyl-Y¹—, which cycloalkyl or cycloalkenyl may be optionally substituted by one or more hydroxyl or C₁₋₆ alkyl groups; R² represents hydrogen or C₁₋₆ alkyl; X represents ethylene or a group of formula CR^(e)R^(f) wherein R^(e) and R^(f) independently represent hydrogen or C₁₋₄ alkyl or R^(e) and R^(f) may together with the carbon atom to which they are attached form a C₃₋₈ cycloalkyl group; R³ and R⁴ independently represent hydrogen or C₁₋₄ alkyl; Z represents a bond, CO, SO₂, CR⁹R⁶(CH₂)_(n), (CH₂)_(n)CR⁹R⁶, CHR⁶(CH₂)_(n)O, CHR⁶(CH₂)_(n)S, CHR⁶(CH₂)_(n)OCO, CHR⁶(CH₂)_(n)CO, COCHR⁶(CH₂)_(n) or SO₂CHR⁶(CH₂)_(n); R⁵ represents C₁₋₆ alkyl, C₂₋₆ alkenyl, aryl, heteroaryl, aryl-C₂₋₆ alkenyl- or a group of formula —Y²-J¹; R⁶ represents hydrogen, C₁₋₄ alkyl, CONR⁷R⁸ or COOC₁₋₆ alkyl; a and b represent 1 or 2, such that a+b represents 2 or 3; n represents an integer from 0 to 4; J¹ and J² independently represent a moiety of formula (K):

wherein X¹ represents oxygen, NR¹³ or sulphur, X² represents CH₂, oxygen, NR¹⁰ or sulphur, m¹ represents an integer from 1 to 3 and m² represents an integer from 1 to 3, provided that m¹+m² is in the range from 3 to 5, also provided that when both X¹ and X² represent oxygen, NR¹³, NR¹⁰or sulphur, m¹ and m² must both not equal less than 2, wherein K is optionally substituted by one or more —Y³-aryl, —Y³-heteroaryl, —Y³—CO-aryl, —COC₃₋₈cycloalkyl, —Y³—CO-heteroaryl, —C₁₋₆ alkyl, —Y³—COOC₁₋₆ , alkyl, —Y³—COC₁₋₆ alkyl, —Y³—W, —Y³—CO—W, —Y³—NR¹¹R¹², —Y³—CONR¹¹R¹², hydroxy, oxo, —Y³—SO₂NR¹¹R¹², —Y³—SO₂C₁₋₆ alkyl, —Y³—SO₂aryl, —Y³—SO₂heteroaryl, —Y³-NR¹⁴C₁₋₆ alkyl, —Y³—NR¹⁴SO₂C₁₋₆ alkyl, —Y³—NR¹⁴CONR¹¹R¹², —Y³—NR¹⁴COOR¹⁵ or —Y³—OCONR¹¹R¹² groups, and is optionally fused to a monocyclic aryl or heteroaryl ring; R⁷, R⁸, R⁹, R¹⁰, R¹³, R¹⁴ and R¹⁵ independently represent hydrogen or C₁₋₆ alkyl; R¹¹ and R¹² independently represent hydrogen or C₁₋₆ alkyl or R¹¹ and R¹² together with the nitrogen atom to which they are attached may form a morpholine, piperidine or pyrrolidine ring; M represents a C₃₋₈ cycloalkyl or a C₃₋₈ cycloalkenyl group fused to a monocyclic aryl or monocyclic heteroaryl group; W represents a saturated or unsaturated, non-aromatic 5-7 membered ring containing between 1 and 3 heteroatoms selected from nitrogen, oxygen or sulphur, optionally substituted with one or more C₁₋₆ alkyl, halogen or hydroxy groups; t represents 0 or
 1. Y¹, Y² and Y³ independently represent a bond or a group of formula —(CH₂)_(p)CR^(c)R^(d)(CH₂)_(q)— wherein R^(c) and R^(d) independently represent hydrogen or C₁₋₄ alkyl or R^(c) and R^(d) may together with the carbon atom to which they are attached form a C₃₋₈ cycloalkyl group, and p and q independently represent an integer from 0 to 5 wherein p+q is an integer from 0 to 5; and salts and solvates thereof.
 2. A compound of formula (I) according to claim 1 wherein R¹ represents C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₂₋₆ alkynyl-Y¹—, aryl-Y¹—, heteroaryl-Y¹—, aryl-(O)_(t)-aryl-Y¹—, aryl-(O)_(t)-heteroaryl-Y¹—, heteroaryl-(O)_(t)-aryl-Y¹—, heteroaryl-(O)_(t)-heteroaryl-Y¹—, C₂₋₆ alkenyl-Y¹—, aryl-O—Y¹—, heteroaryl-O—Y¹—, C₁₋₆ alkyl-O₂—Y¹—, M-Y¹— or C₃₋₈ cycloalkyl-Y¹— or C₃₋₈ cycloalkenyl-Y¹—, which cycloalkyl or cycloalkenyl may be optionally substituted by one or more hydroxyl or C₁₋₆ alkyl groups; and J¹ represents a moiety of formula (K):

wherein X¹ represents oxygen, NR¹³ or sulphur, X² represents CH₂, oxygen, NR¹⁰ or sulphur, m¹ represents an integer from 1 to 3 and m² represents an integer from 1 to 3, provided that m¹+m² is in the range from 3 to 5, also provided that when both X¹ and X² represent oxygen, NR¹³, NR¹⁰ or sulphur, m¹ and m² must both not equal less than 2, wherein K is optionally substituted by one or more —Y³-aryl, —Y³-heteroaryl, —Y³—CO-aryl, —Y³—CO-heteroaryl, —C₁₋₆ alkyl, —Y³—COOC₁₋₆ alkyl, —Y³—COC₁₋₆ alkyl, —Y³—W, —Y³—CO—W, —Y—NR¹¹R¹², —Y³—CONR¹¹R¹², hydroxy, oxo, —Y³—SO₂NR¹¹R¹², —Y³—SO₂C₁₋₆ alkyl, —Y³—SO₂aryl, —Y³—SO₂heteroaryl, —Y³—NR¹⁴C₁₋₆ alkyl, —Y³—NR¹⁴SO₂C₁₋₆ alkyl, —Y³—NR¹⁴CONR¹¹R¹², —Y³—NR¹⁴COOR¹⁵ or —Y³—OCONR¹¹R¹² groups, and is optionally fused to a monocyclic aryl or heteroaryl ring.
 3. A compound of formula (I) according to claim 1 wherein R¹ represents C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl-Y¹—, heteroaryl-Y¹—, aryl-(O)_(t)-aryl-Y¹—, aryl-(O)_(t)-heteroaryl-Y¹—, heteroaryl-(O)_(t)-aryl-Y¹—, heteroaryl-(O)_(t)-heteroaryl-Y¹—, C₂₋₆ alkenyl-Y¹—, aryl-O—Y¹—, heteroaryl-O—Y¹—, C₁₋₆ alkyl-SO₂—Y¹, M-Y¹— or C₃₋₈ cycloalkyl-Y¹— or C₃₋₈ cycloalkenyl-Y¹—, which cycloalkyl or cycloalkenyl may be optionally substituted by one or more hydroxyl or C₁₋₆ alkyl groups; Z represents a bond, CO, CR⁹R⁶(CH₂)_(n), CHR⁶(CH₂)_(n)O, CHR⁶(CH₂)_(n)S, CHR⁶(CH₂)_(n)OCO, CHR⁶(CH₂)_(n)CO; and J¹ represents a moiety of formula (K):

wherein X¹ represents oxygen, nitrogen, NR¹³ or sulphur, X² represent CH₂, oxygen, nitrogen, NR¹⁰ or sulphur, m¹ represents an integer from 1 to 3, m² represents an integer from 1 to 3, provided that m¹+m² is in the range from 3 to 5, also provided that when X² represents oxygen, nitrogen, NR¹⁰ or sulphur, m¹ and m² must both not equal less than 2, wherein K is optionally substituted by one or more —Y³-aryl, —Y³-heteroaryl, —Y³—CO-aryl, —Y3—CO-heteroaryl, —C₁₋₆ alkyl, —Y³—COOC₁₋₆ alkyl, —Y³—COC₁₋₆ alkyl, —Y3—W, —Y³—CO—W, —Y³—NR¹¹R¹², —Y³—CONR¹¹R¹², hydroxy, oxo, —Y³—SO₂NR¹¹R¹², —Y³—SO₂C₁₋₆ alkyl, —Y³—SO₂aryl, —Y³—SO₂heteroaryl, —Y³—NR¹⁴C₁₋₆ alkyl, —Y³—NR¹⁴SO₂C₁₋₆ alkyl, —Y³—NR¹⁴CONR¹¹R¹², —Y³—NR¹⁴COOR¹⁵ or —Y³—OCONR¹¹R¹² groups, and is optionally fused to a monocyclic aryl or heteroaryl ring.
 4. A compound of formula (I) according to any one of claims 1 to 3 wherein R¹ represents aryl-Y¹—.
 5. A compound of formula (I) according to claim 4 wherein R¹ represents optionally substituted phenyl-Y¹— in which phenyl may be optionally substituted.
 6. A compound of formula (I) according to any one of claims 1 to 5 wherein Y¹ represents —CH₂—.
 7. A compound of formula (I) according to claim 1 wherein X represents methylene.
 8. A compound of formula (I) according to claim 1 wherein a and b both represent
 1. 9. A compound of formula (I) according to claim 1 or claim 3 wherein Z represents a bond, CO, CHR⁶(CH₂)_(n), CHR⁶(CH₂)_(n)O or CHR⁶(CH₂)_(n)CO.
 10. A compound of formula (I) according to claim 9 wherein Z represents CH₂.
 11. A compound of formula (I) according to claim 1 wherein R⁶ represents phenyl optionally substituted with one or more halogen atoms.
 12. A compound of formula (I) according to claim 11 wherein R⁶ represents 3,4-dichlorophenyl.
 13. A compound of formula (I) according to any one of claims 1 to 12 as described in Examples 1 to 240 or a salt or solvate of any one thereof.
 14. A compound of formula (I) according to claim 13 which is 2-[3-(Aminosulfonyl)phenyl]-N-{[(2S)-4-(3,4-dichlorobenzyl)morpholin-2-yl]methyl}acetamide or a solvate thereof.
 15. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 14 or a pharmaceutically acceptable salt or solvate thereof in admixture with one or more pharmaceutically acceptable diluents or carriers.
 16. A compound of formula (I) as defined in any one of claims 1 to 14 or a pharmaceutically acceptable salt or solvate thereof for use as a pharmaceutical.
 17. Use of a compound of formula (I) as defined in any one of claims 1 to 14 or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of inflammatory diseases.
 18. A method of treatment or prophylaxis of inflammatory diseases eg. asthma which comprises administering to a patient an effective amount of a compound of formula (I) as defined in any one of claims 1 to 14 or a pharmaceutically acceptable salt or solvate thereof.
 19. A process for preparing a compound of formula (I) according to any one of claims 1 to 14 which comprises: (a) acylation of a compound of formula (II)

wherein R², R³, R⁴, R⁵, X, Z, a and b are as defined in claim 1, with a compound of formula R¹COOH or an activated derivative thereof, wherein R¹ is as defined in claim 1; or (b) reacting a compound of formula (III)

wherein R¹, R², R³, R⁴, X, a and b are as defined in claim 1, with a compound of formula L¹-Z-R⁵, wherein Z and R¹ are as defined in claim 1 and L¹ represents a suitable leaving group; or (c) deprotecting a compound of formula (I) which is protected; or (d) interconversion of other compounds of formula (I).
 20. A process for preparing a compound of formula (I) according to any one of claims 1 to 14 which comprises: (e) forming a compound of formula (I) wherein R¹ represents heteroaryl-Y¹—, aryl-(O)_(t)-heteroaryl-Y¹— or heteroaryl-(O)_(t)-heteroaryl-Y¹— (wherein said Y¹ group is attached to heteroaryl via a heterocyclic nitrogen atom) and R² represents hydrogen which comprises reacting a compound of formula (IV)

or a protected derivative thereof wherein R³, R⁴, R⁵, X, Y¹, Z, a and b are as defined in claim 1, L² represents a suitable leaving group, such as a halogen atom eg. bromine and P¹ represents a solid phase resin bound protecting group, with a heterocyclic compound defined by the R¹ groups heteroaryl, aryl-(O)_(t)-heteroaryl or heteroaryl-(O)_(t)-heteroaryl above wherein said heteroaryl group contains at least one NH atom, followed by removal of the solid phase resin bound protecting group; or (f) forming a compound of formula (I) wherein Z represents CR⁹R⁶(CH₂)_(n) and R⁹ represents hydrogen which comprises reacting a compound of formula (III) or a protected derivative thereof with a compound of formula R⁶CO(CH₂)_(n)R⁵, followed by reduction of the resultant imine; or (g) forming a compound of formula (I) wherein Z represents CO by reacting a compound of formula (III) or a protected derivative thereof with a compound of formula R⁵COOH or an activated derivative thereof.
 21. A compound of formula (II)

wherein R², R³, R⁴, R⁵, X, Z, a and b are as defined in claim 1 or a protected derivative thereof, or a salt or solvate thereof.
 22. A compound of formula (III)

wherein R¹, R², R³, R⁴ ₁ X, a and b are as defined in claim 1 or a protected derivative thereof, or a salt or solvate thereof.
 23. A compound of formula (IV)

wherein R³, R⁴, R⁵, X, Y¹, Z, a and b are as defined in claim 1, L² represents a suitable leaving group, such as a halogen atom eg. bromine and P¹ represents a solid phase resin bound protecting group, or a salt or solvate thereof. 